Liver X receptor modulators

ABSTRACT

Provided herein are novel compounds and pharmaceutically acceptable salts thereof that are liver X receptor modulators. Also provided are compositions comprising compounds of the invention and a carrier. Additionally, use of the compounds herein and methods for treating a disease or disorder associated with the liver X receptor are further described.

REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.14/385,671, filed on Sep. 16, 2014, which is a 35 U.S.C. §371 NationalStage filing of International Application No. PCT/US2013/031250, filedMar. 14, 2013, which claims the benefit of U.S. Provisional ApplicationNo. 61/612,063, filed on Mar. 16, 2012. The entire contents of each ofthe aforementioned applications are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to compounds that modulate the activity ofliver X receptors.

BACKGROUND OF THE INVENTION

Atherosclerosis is the leading cause of death in the developed world,and atherosclerosis is predicted to be the leading cause of death in thedeveloping world in the 21st century. Liver X receptors (LXRs) areligand-activated transcription factors that play a crucial role inregulating the expression of genes involved in lipid metabolism andcellular cholesterol homeostasis. LXR agonists have been shown toenhance reverse cholesterol transport (RCT), facilitating cholesteroltrafficking from the periphery back to the liver for processing andexcretion. RCT occurs via upregulation of cholesterol transporters(ATP-Binding Cassettes: ABCA1 and ABCG1) in peripheral macrophages.Active RCT has the potential to inhibit the progression ofatherosclerosis.

There are two isoforms of LXR, LXRα (NR1H3) and LXRβ (NR1H2) that areencoded by separate genes. LXRα expression is tissue-selective,detectable in liver, intestine, kidney, adipose tissue and adrenalglands, all of which are important for lipid homeostasis, whereas LXRβis expressed ubiquitously. Both LXRs require the retinoid X receptor(RXR) as an obligate heterodimer partner to recognize and bindcooperatively to LXR response elements (LXREs) consisting of two directrepeats of a core hexameric sequence spaced by four nucleotides (DR4).The ligand binding domains of the two LXRs are fairly well conserved(˜78% amino acid homology) and respond to endogenous ligands consistingof oxidized derivatives of cholesterol (oxysterols) that serve asintermediates in steroid hormone and bile acid synthesis. Among them,22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, and 24(S),25-epoxycholesterol are the most potent. These data suggested that LXRsare likely to play an important role in cholesterol regulation, whichwas later confirmed through gene knock-out studies in mice.Non-steroidal ligands have also been identified, and, using these aschemical probes many LXR-regulated genes have been discovered. SeveralLXRE-containing genes are involved in cholesterol metabolism, reversecholesterol transport (RCT) and lipogenesis. Other genes involved ininflammation and carbohydrate metabolism lack LXREs, but are repressedby LXRs in a ligand-dependent manner. Based on these discoveries, theliver X receptors have recently emerged as unprecedented targets actingas intracellular cholesterol sensors, providing the basis for thetreatment of a variety of diseases, including atherosclerosis, diabetes,Alzheimer's disease, skin disorders, reproductive disorders and cancer(Viennois et al., 2011, Expert Opin. Ther. Targets, 15(2):219-232).Additionally, it has been determined that LXR agonists modulateintestinal and renal sodium phosphate (NaPi) transporters and, in turn,serum phosphate levels (Caldas et al., 2011, Kidney International,80:535-544). Thus, LXR is also a target for kidney disorders, andparticularly for the prevention of hyperphosphatemia and associatedcardiovascular complications. Recently, LXRs have been identified astargets in the treatment of osteoporosis and related diseases (Kleyer etal., 2012, J. Bone Miner. Res., 27(12):2442-51).

Alzheimer's disease is one of the most common forms of dementia,characterized by the accumulation and deposition of amyloid-beta (Aβ)peptides in the brain, leading to the perturbation of synaptic functionand neuronal loss in the brains of affected individuals. Neurons in thebrain produce Aβ peptides via cleavage of amyloid precursor protein(APP), and Aβ peptides are normally cleared through efflux into theperipheral circulation and by degradation by proteinases within thebrain.

Apolipoprotein E (apoE) is associated with age-related risk forAlzheimer's disease and plays critical roles in Aβ homeostasis. LXRincreases the expression of apoE and increases the lipidation of apoE.Degradation of Aβ both intra- and extracellularly is enhanced bylipidated apoE. LXR agonist treatment stimulated proteolytic degradationof Aβ, reduced plaque pathology, and improved memory in APP-expressingtransgenic mice (Jiang et al., 2008, Neuron, 58:681-693).

In skin, keratinocytes are a critical component of the epidermis. Theouter layer, stratum corneum, is primarily responsible for thepermeability barrier to water and electrolyte transit. Keratinocytes inthe epidermis undergo differentiation which culminates in keratinocytecornification (“the bricks”) and in formation of the extracellularlipid-enriched lamellar membranes (“the mortar”) in the stratum corneum.Both LXRα and LXRβ are expressed in keratinocytes, and LXR expressionand activation promotes epidermis barrier function. Activation of LXR isinvolved in keratinocyte differentiation, formation of the lamellarmembrane and overall improvement of epidermal barrier function. Thus,LXR activation is expected to result in increased keratinocytedifferentiation, increased lipid secretion (via ABCA1, ABCA12), andincreased lamellar body formation, leading to a healthy epidermis(smooth skin).

The potential therapeutic utility of LXR agonists has led to thedevelopment of several high affinity LXR ligands with potent agonism forboth receptor subtypes. The therapeutic utility of LXR agonists isconstrained by their potential to induce lipogenic genes includingsterol response element binding protein-1c (SREBP1c) and fatty acidsynthase (FAS). Preclinical studies have demonstrated that syntheticmodulators of LXRs reduce lesion progression in murine models ofatherosclerosis with limited increase in hepatic lipogenesis. There is aclear need for new LXR chemotypes that retain the anti-atheroscleroticefficacy of current LXR agonists but are devoid of lipogenic activity.Compounds exhibiting a pharmacological profile with positive effects onRCT while being neutral or suppressive on lipogenic genes will bevaluable therapeutic agents in patients with atheroscleroticdyslipidemia.

The present invention provides compounds that are liver X receptoragonists and are useful as therapeutic agents for the promotion ofreverse cholesterol transport and the suppression of hepaticlipogenesis, and for the prevention, amelioration or treatment ofdiseases or disorders including atherosclerosis, Alzheimer's disease,dermatitis, and dyslipidemia in a patient.

SUMMARY OF THE INVENTION

Disclosed are LXR modulators that are useful as therapeutic agents forthe promotion of reverse cholesterol transport and the suppression ofhepatic lipogenesis, and for the prevention, amelioration or treatmentof diseases or disorders including atherosclerosis and dyslipidemia in asubject. The disclosed LXR modulators are selective for the LXRβ subtypeover the LXRα subtype (see e.g., Example 6, isomer 1; Example 7, isomer1; and Example 13, isomer 1).

One embodiment of the invention is a compound represented by structuralformula I:

or a pharmaceutically acceptable salt thereof.

X is N or CR^(c).

R¹ is alkyl or —NR^(a)R^(b).

R² is H; halogen; —CN; —NRC(O)R; —C(O)OR; —C(O)NR^(a)R^(b); monocyclicheteroaromatic optionally substituted with one or more groups selectedfrom alkyl, —CN, —NRC(O)R, —C(O)OR, —C(O)NR^(a)R^(b) and halogen;monocyclic non-aromatic heterocycle optionally substituted with one ormore groups selected from alkyl, halogen, —CN and ═O; or alkyloptionally substituted by one or more groups selected from halogen,hydroxy, alkoxy, —NR^(a)R^(b), —NRC(O)R, —NRC(O)O(alkyl), —NRC(O)N(R)₂,—C(O)OR, thiol, alkylthiol, nitro, —CN, ═O, —OC(O)H, —OC(O)(alkyl),—OC(O)O(alkyl), —OC(O)N(R)₂ and —C(O)NR^(a)R^(b).

R³ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,monocyclic non-aromatic heterocycle, monocyclic heteroaromatic orphenyl, wherein the phenyl, monocyclic non-aromatic heterocycle andmonocyclic heteroaromatic group represented by R³ are optionallysubstituted with one or more groups selected from alkyl, halogen,haloalkyl, alkoxy, haloalkoxy, nitro and —CN.

R⁴ and R⁵ independently are halogen, —CN, —OR, —SR, —N(R)₂, —C(O)R,—C(O)OR, —OC(O)O(alkyl), —C(O)O(haloalkyl), —OC(O)R, —C(O)N(R)₂,—OC(O)N(R)₂, —NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO₂R, —SO₂N(R)₂,—NRS(O)R, —NRSO₂R, —NRC(O)N(R)₂, —NRSO2N(R)2, haloalkyl, haloalkoxy,cycloalkoxy, cycloalkyl, monocyclic non-aromatic heterocycle, monocyclicheteroaromatic or alkyl, wherein the alkyl, monocyclic non-aromaticheterocycle and monocyclic heteroaromatic group represented by R⁴ or R⁵are optionally substituted with one or more groups selected from —CN,—OR, —SR, —N(R)₂, ═O, —C(O)R, —C(O)OR, —C(O)O(haloalkyl), —OC(O)R,—OC(O)O(alkyl), —C(O)N(R)₂, —OC(O)N(R)₂, —NRC(O)R, —NRC(O)O(alkyl),—S(O)R, —SO₂R, —SO₂N(R)₂, —NRS(O)R, —NRSO₂R, —NRC(O)N(R)₂ and—NRSO₂N(R)₂.

R⁶ is H, halogen, —CN, —OR, —SR, —N(R)₂, —C(O)R, —C(O)OR,—OC(O)O(alkyl), —C(O)O(haloalkyl), —OC(O)R, —C(O)N(R)₂, —OC(O)N(R)₂,—NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO₂R, —SO₂N(R)₂, —NRS(O)R, —NRSO₂R,—NRC(O)N(R)₂, —NRSO₂N(R)₂, haloalkyl, haloalkoxy, cycloalkoxy,cycloalkyl or alkyl, wherein the alkyl group represented by R⁶ isoptionally substituted with one or more groups selected from —CN, —OR,—SR, —N(R)₂, ═O, —C(O)R, —C(O)OR, —C(O)O(haloalkyl), —OC(O)R,—OC(O)O(alkyl), —C(O)N(R)₂, —OC(O)N(R)₂, —NRC(O)R, —NRC(O)O(alkyl),—S(O)R, —SO₂R, —SO₂N(R)₂, —NRS(O)R, —NRSO₂R, —NRC(O)N(R)₂ and—NRSO₂N(R)₂; or R⁵ and R⁶, taken together with the carbon atoms to whichthey are bonded, form a moncyclic non-aromatic heterocycle optionallysubstituted with one or more groups selected from alkyl, halogen,hydroxyalkyl, alkoxyalkyl, haloalkyl and ═O.

Each R independently is H or alkyl.

R^(a) and R^(b) are independently H, alkyl or R^(a) and R^(b) can betaken together with the nitrogen to which they are attached to form amonocyclic non-aromatic heterocycle.

R^(c) is H, alkyl, or halogen.

Another aspect of the invention is a pharmaceutical compositioncomprising a compound of the invention and a pharmaceutically acceptablecarrier or diluent.

A further aspect of the present invention also provides for a method oftreating a subject with a disease or disorder that is treatable byupregulating LXR activity. The method comprises administering aneffective amount of a compound of the invention or a pharmaceuticallyacceptable salt thereof to the subject in need thereof.

Also provided in the invention is the use of a compound of the inventionfor the manufacture of a medicament for treating a subject with adisease or disorder that is treatable by upregulating LXR activity in asubject in need thereof.

Disclosed herein is also a compound of the invention for use in treatinga disease or disorder that is treatable by upregulating LXR activity ina subject in need thereof.

Another embodiment of the invention is an intermediate compound used inthe preparation of an LXR modulator and is represented by structuralformula Ia:

or a salt thereof.

X is N or CR^(c).

R¹⁰ is alkyl or —NR^(a)R^(b).

R²⁰ is H; halogen; —CN; —NRC(O)R; —C(O)OR; —C(O)NR^(a)R^(b); monocyclicheteroaromatic optionally substituted with one or more groups selectedfrom alkyl, —CN, —NRC(O)R, —C(O)OR, —C(O)NR^(a)R^(b) and halogen;monocyclic non-aromatic heterocycle optionally substituted with one ormore groups selected from alkyl, halogen, —CN and ═O; or alkyloptionally substituted by one or more groups selected from halogen,hydroxy, alkoxy, —NR^(a)R^(b), —NRC(O)R, —NRC(O)O(alkyl), —NRC(O)N(R)₂,—C(O)OR, thiol, alkylthiol, nitro, —CN, ═O, —OC(O)H, —OC(O)(alkyl),—OC(O)O(alkyl), —OC(O)N(R)₂, —C(O)NR^(a)R^(b), and —O (protectinggroup).

R³⁰ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl orphenyl, wherein the phenyl group represented by R³⁰ is optionallysubstituted with one or more groups selected from alkyl, halogen,haloalkyl, alkoxy, haloalkoxy, nitro and —CN.

Each R independently is H or alkyl.

R^(a) and R^(b) are independently H, alkyl or R^(a) and R^(b) can betaken together with the nitrogen to which they are attached to form amonocyclic non-aromatic heterocycle.

R^(c) is H, alkyl, or halogen.

DETAILED DESCRIPTION OF THE INVENTION A. Compounds

The compound(s) of the invention provided herein (or intermediate(s)used in their preparation) include both the neutral form and apharmaceutically acceptable salt thereof.

In one embodiment, the compound is represented by structural formula II,III, IV, V, VI, or VII or a pharmaceutically acceptable salt thereofwherein the values for the variables are as defined for Formula I above.

In a first alternative embodiment of any compound of formulas I throughVII, the variables are defined as follows.

R³ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, orphenyl, wherein the phenyl group represented by R³ is optionallysubstituted with one or more groups selected from alkyl, halogen,haloalkyl, alkoxy, haloalkoxy, nitro and —CN;

R⁴ and R⁵ independently are halogen, —CN, —OR, —SR, —N(R)₂, —C(O)R,—C(O)OR, —OC(O)O(alkyl), —C(O)O(haloalkyl), —OC(O)R, —C(O)N(R)₂,—OC(O)N(R)₂, —NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO₂R, —SO₂N(R)₂,—NRS(O)R, —NRSO₂R, —NRC(O)N(R)₂, —NRSO2N(R)₂, haloalkyl, haloalkoxy,cycloalkoxy, cycloalkyl or alkyl, wherein the alkyl represented by R⁴ orR⁵ is optionally substituted with one or more groups selected from —CN,—OR, —SR, —N(R)₂, ═O, —C(O)R, —C(O)OR, —C(O)O(haloalkyl), —OC(O)R,—OC(O)O(alkyl), —C(O)N(R)₂, —OC(O)N(R)₂, —NRC(O)R, —NRC(O)O(alkyl),—S(O)R, —SO₂R, —SO₂N(R)₂, —NRS(O)R, —NRSO₂R, —NRC(O)N(R)₂ and—NRSO₂N(R)₂;

R⁶ is H, halogen, —CN, —OR, —SR, —N(R)₂, —C(O)R, —C(O)OR,—OC(O)O(alkyl), —C(O)O(haloalkyl), —OC(O)R, —C(O)N(R)₂, —OC(O)N(R)₂,—NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO₂R, —SO₂N(R)₂, —NRS(O)R, —NRSO₂R,—NRC(O)N(R)₂, —NRSO₂N(R)₂, haloalkyl, haloalkoxy, cycloalkoxy,cycloalkyl or alkyl, wherein the alkyl group represented by R⁶ isoptionally substituted with one or more groups selected from —CN, —OR,—SR, —N(R)₂, ═O, —C(O)R, —C(O)OR, —C(O)O(haloalkyl), —OC(O)R,—OC(O)O(alkyl), —C(O)N(R)₂, —OC(O)N(R)₂, —NRC(O)R, —NRC(O)O(alkyl),—S(O)R, —SO₂R, —SO₂N(R)₂, —NRS(O)R, —NRSO₂R, —NRC(O)N(R)₂ and—NRSO₂N(R)₂.

In a second alternative embodiment of any compound of formulas I throughVII, the variables are defined as follows.

R¹ is methyl or —NH₂.

R² is H or methyl, wherein the methyl group represented by R² isoptionally substituted with one or more groups selected from halogen,hydroxy, alkoxy, —NR^(a)R^(b), —NRC(O)R, —NRC(O)O(alkyl), —NRC(O)N(R)₂,—C(O)OR, thiol, alkylthiol, nitro, —CN, ═O, —OC(O)H, —OC(O)(alkyl),—OC(O)O(alkyl), —C(O)NR^(a)R^(b) and —OC(O)N(R)₂. Preferably, R² is H or—CH₂OH.

R³ is methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl,iso-butyl, —CH₂CF₃, —CH(CH₂F)₂, —CH(CHF₂)₂, —CH(CF₃)₂, —CF(CH₃)₂, —CF₃,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —C(OH)(CH₃)₂,—CH(OH)(CH₃), or phenyl, wherein the phenyl group represented by R³ isoptionally substituted with one or more groups selected from alkyl,halogen, haloalkyl, alkoxy, haloalkoxy, nitro and —CN.

R^(c), where present, is H.

The values for the remaining variables are as defined for Formula I orfor the first alternative embodiment.

In a third alternative embodiment of any compound of formulas I throughVII, R¹ is methyl; R² is —CH₂OH; and R³ is isopropyl. The values for theremaining variables are as defined for Formula I or for the first orsecond alternative embodiment.

In a fourth alternative embodiment of any compound of formulas I throughVII, R⁴ and R⁵ independently are halogen, hydroxy, alkyl, cycloalkyl,cycloalkoxy, alkoxy, haloalkoxy, haloalkyl, —N(R)₂, —C(O)OH,—C(O)O(alkyl), —C(O)O(haloalkyl), —C(O)(alkyl), —C(O)N(R)₂, —NRC(O)R,—SO₂N(R)₂, —OC(O)N(R)₂, —CN, hydroxyalkyl or dihydroxyalkyl. The valuesfor the remaining variables are as defined for Formula I or for thefirst, second or third alternative embodiments.

In a fifth alternative embodiment of any compound of formulas I throughVII, R⁴ is alkyl, haloalkyl, cycloalkyl, alkoxy, or haloalkoxy. Thevalues for the remaining variables are as defined for Formula I or forthe first, second, third or fourth alternative embodiments.

In a sixth alternative embodiment of any compound of formulas I throughVII, R⁴ and R⁵ independently are methyl, ethyl, hydroxy, —CF₃,isopropyl, cyclopropyl, —CH₂OH, —CH(OH)(CH₂)(OH), —C(OH)(CH₃)₂,—CH(OH)(CH₃), —CH(OH)(CH₂)(CH₃), —CH(OH)(CH₂)₂(CH₃), —C(O)NH₂,—C(O)N(CH₃)₂, —C(O)OH, —C(O)NH(CH₃), —C(O)CH₃, —C(O)CH₂CH₃,—C(O)O(CH₂)(CH₃), —C(O)O(tert-butyl), —C(O)O(C)(CH₃)₂(CF₃), —NHC(O)CH₃,—OCHF₂, —OCF₃, —OCH₂CH₃, —OCH(CH₃)₂ or —OCH₃. Preferably, R⁴ is as justdescribed and R⁵ is —C(OH)(CH₃)₂. The values for the remaining variablesare as defined for Formula I or for the first, second, third, fourth orfifth alternative embodiments.

In a seventh alternative embodiment of any compound of formulas Ithrough VII, R⁴ is methyl, halogenated methyl, cyclopropyl, —OCHF₂ or—OCH₃. Preferably, R⁴ is CF₃. The values for the remaining variables areas defined for Formula I or for the first, second, third, fourth, fifthor six alternative embodiments.

Another embodiment of the invention is a compound represented byformulas I, II, III, IV, V, VI or VII or a pharmaceutically acceptablesalt thereof, wherein the variables are as defined for formula I or inthe first, second, third, fourth, fifth, sixth or seventh alternativeembodiments, provided that the compound comprises at least one grouprepresented by —C(O)OR.

Another embodiment of the invention is a compound represented by formulaI, II, III, IV V, VI or VII or a pharmaceutically acceptable saltthereof, wherein the variables are as defined for formula (I) or in thefirst, second, third, fourth, fifth, sixth or seventh alternativeembodiment, provided that the compound comprises no groups representedby —C(O)OR.

The compounds of the invention (or intermediate(s) used in theirpreparation) contain at least one chiral center and, therefore, exist asenantiomers. When compounds of the invention are depicted or namedwithout indicating the stereochemistry, it is to be understood thatenantiomerically pure forms and mixtures of enantiomers, includingracemic mixtures, are encompassed.

When a compound is designated by a name or structure that indicates asingle enantiomer, unless indicated otherwise, the compound is at least50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5% or 99.9% optically pure (alsoreferred to as “enantiomerically pure”). Optical purity is the weight inthe mixture of the named or depicted enantiomer divided by the totalweight in the mixture of both enantiomers.

When a compound is designated by a name or structure that indicates aspecific stereochemistry at a chiral center, unless indicated otherwise,the compound is at least 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5% or99.9% stereoisomerically pure. Stereoisomeric purity is the weight inthe mixture of the named or depicted stereoisomer(s) divided by thetotal weight in the mixture of all stereoisomers.

In an eighth alternative embodiment, a compound of the invention isdepicted by a structural formula in Table 1 or a pharmaceuticallyacceptable salt thereof. In an eighth alternative embodiment, a compoundof the invention is selected from any one of compounds E6a, E7a, E13a,E18 and E27a or a pharmaceutically acceptable salt thereof.

TABLE 1 Compound No. Example No. Structure E1 Example 01

E2 Example 02

E3 Example 03

E4 Example 04

E5 Example 05

E6a Example 06, isomer 1

E6b Example 06, isomer 2

E7a Example 07, isomer 1

E7b Example 07, isomer 2

E8a Example 08, isomer 1

E8b Example 08, isomer 2

E8c Example 08, isomer 3

E8d Example 08, isomer 4

E9a Example 09, isomer 1

E9b Example 09, isomer 2

E10a Example 10, isomer 1

E10b Example 10, isomer 2

E10c Example 10, isomer 3

E10d Example 10, isomer 4

E11a Example 11, isomer 1

E11b Example 11, isomer 2

E12 Example 12

E13a Example 13, isomer 1

E13b Example 13, isomer 2

E14a Example 14, isomer 1

E14b Example 14, isomer 2

E15a Example 15, isomer 1

E15b Example 15, isomer 2

E16a Example 16, isomer 1

E16b Example 16, isomer 2

E17a Example 17, isomer 1

E17b Example 17, isomer 2

E18 Example 18

E19 Example 19

E20a Example 20, isomer 1

E20b Example 20, isomer 2

E21 Example 21

E22a Example 22, isomer 1

E22b Example 22, isomer 2

E23a Example 23, isomer 1

E23b Example 23, isomer 2

E24a Example 24, isomer 1

E24b Example 24, isomer 2

E24c Example 24, isomer 3

E24d Example 24, isomer 4

E25a Example 25, isomer 1

E25b Example 25, isomer 2

E26 Example 26

E27a Example 27, isomer 1

E27b Example 27, isomer 2

E28 Example 28

E29a Example 29, isomer 1

E29b Example 29, isomer 2

E30 Example 30

In another embodiment, an intermediate compound used in the preparationof the LXR modulators is represented by structural formula VIII, IX, orX or a salt thereof wherein the values for the variables are as definedfor Formula Ia above.

In a first alternative embodiment of an intermediate compound of formulaVIII through X, R¹⁰ is —CH₃. The values for the remaining variables areas defined for Formula Ia.

In a second alternative embodiment of an intermediate compound offormulas VIII through X, R²⁰ is —CH₂OH, —CH₂O (protecting group), —COOH,or —C(O)O(alkyl). The values for the remaining variables are as definedfor Formula Ia or in the first alternative embodiment for formulas VIIIthrough X.

In a third alternative embodiment of an intermediate compound offormulas VIII through X, R³⁰ is isopropyl. The values for the remainingvariables are as defined for Formula Ia or the first or secondalternative embodiment for formulas VIII through X.

In a fourth alternative embodiment of an intermediate compound offormulas VIII through X, R²⁰ is —CH₂O (TBDPS) or —C(O)OCH₃. The valuesfor the remaining variables are as defined for Formula Ia or for thefirst or third alternative embodiment of any compound of formulas VIIIthrough X.

In a fifth alternative embodiment of an intermediate compound offormulas VIII through X, an intermediate compound is selected from

or a salt thereof.

In a sixth alternative embodiment of an intermediate compound offormulas VIII through X, an intermediate compound is

or a salt thereof.

B. Definitions

Unless otherwise specified, the below terms used herein are defined asfollows.

“Subject”, “patient” and “mammal” are used interchangeably herein. Inone embodiment, the subject is a non-human animal such as a non-humanprimate (e.g., a monkey, chimpanzee), a farm animal (e.g., a horse, cow,pig, chicken, or sheep), a laboratory animal (e.g., a rat or mouse), ora companion animal (e.g., dog, cat, guinea pig or rabbit). In apreferred embodiment, the subject is a human.

“Compound(s) of the invention” refers to compounds represented byStructural Formula I, II, III, IV, V, VI, VII; a compound depicted inTable 1; a compound named or depicted in the examples herein as thefinal compound(s) of the example; or a pharmaceutically acceptable saltthereof. “Compound(s) of the invention” also includes the neutral formof the compounds as depicted herein.

“Pharmaceutically acceptable” refers to a component that is, within thescope of sound medical judgment, suitable for use in contact with thetissues of the subject, such as humans and other mammals, without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio.

Included in the invention are pharmaceutically acceptable salts of thecompounds disclosed herein. The disclosed compounds have basic aminegroups and therefore can form pharmaceutically acceptable salts withpharmaceutically acceptable acid(s). Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the invention includesalts of inorganic acids (such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organicacids (such as, acetic acid, benzenesulfonic, benzoic, citric,ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic,lactobionic, maleic, malic, methanesulfonic, succinic,p-toluenesulfonic, and tartaric acids). Compounds of the invention withacidic groups such as carboxylic acids can form pharmaceuticallyacceptable salts with pharmaceutically acceptable base(s). Suitablepharmaceutically acceptable basic salts include ammonium salts, alkalimetal salts (such as sodium and potassium salts) and alkaline earthmetal salts (such as magnesium and calcium salts). Lists of suitablesalts are found in Remington's Pharmaceutical Sciences, 18th ed., MackPublishing Company, Easton, Pa., 1990, p 1445, the disclosure of whichis hereby incorporated by reference.

“Liver X receptors or LXRs” includes both the α and β subtypes of theliver X receptor. In one embodiment, the disclosed compounds selectivelybind and upregulate the activity of the LXRβ subtype over the LXRαsubtype. To “modulate” a receptor means that there is a change oralteration in the activity of a molecule of interest, e.g., thebiological activity of liver X receptor. Modulation may be anupregulation (increase) or a downregulation (decrease) in the magnitudeof a certain activity or function of the molecule of interest. Exemplaryactivities and functions of a molecule include, but are not limited to,binding characteristics, enzymatic activity, cell receptor activation,transcriptional activity, and signal transduction. In an embodiment, thecompounds of the invention are LXR agonists that, for example,upregulate or downregulate genes which are transcriptional targets ofLXR (i.e., “LXR target genes”).

“Treat” or “treating” include both therapeutic and prophylactictreatments and mean to ameliorate, decrease, suppress, attenuate,diminish, arrest, or stabilize the development or progression of adisease (e.g., a disease or disorder delineated herein), lessen theseverity of the disease or improve the symptoms associated with thedisease.

“Disease” or “disorder” means any condition that is modulated orotherwise affected by LXR activity or in which LXR activity isimplicated. The diseases or disorders include those which are associatedwith, or symptoms arising from the complications of, altered cholesteroltransport, cholesterol reverse transport, fatty acid metabolism,cholesterol absorption, cholesterol re-absorption, cholesterolsecretion, cholesterol excretion, or cholesterol metabolism.

“Effective amount” is the quantity of the compound which is sufficientto treat (therapeutically or prophylactically) the target disorder or inwhich a beneficial clinical outcome is achieved when the compound isadministered to a subject in a proper dosing regimen. Effective doseswill also vary, as recognized by one of ordinary skill in the art,depending on the disease being treated, the severity of the disease, theroute of administration, the sex, age and general health condition ofthe patient, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents and the judgment ofthe treating physician or other medical provider. For example, aneffective amount is sufficient to reduce or ameliorate the severity,duration or progression of the disorder being treated, prevent theadvancement of the disorder being treated, cause the regression of thedisorder being treated, or enhance or improve the prophylactic ortherapeutic effect(s) of another therapy. For example, when a compoundof the invention is administered to a subject with a cancer, a“beneficial clinical outcome” includes a reduction in tumor mass, areduction in metastasis, a reduction in the severity of the symptomsassociated with the cancer and/or an increase in the longevity of thesubject compared with the absence of the treatment. When a compound ofthe invention is administered to a subject with a disorder such asatherosclerosis, a “beneficial clinical outcome” includes reduction inthe severity or number of symptoms associated with the disorder, lowercholesterol, or increase in the longevity of the subject compared withthe absence of the treatment. The recommended dosages of agentscurrently used for the treatment of a disorder can be obtained fromvarious references in the art including, but not limited to, Hardman etal., eds., 1996, Goodman & Gilman's The Pharmacological Basis Of BasisOf Therapeutics 9^(th) Ed, Mc-Graw-Hill, New York; Physician's DeskReference (PDR) 57^(th) Ed., 2003, Medical Economics Co., Inc.,Montvale, N.J., each of which are incorporated herein by reference inits entirety. In certain embodiments, an effective amount of a compoundof this invention is in the range of from 0.5 mg to 2000 mg, or from 0.5mg to 1000 mg, or from 0.5 mg to 500 mg, or from 0.5 mg to 100 mg, orfrom 100 mg to 1000 mg, or from 20 mg to 2000 mg per treatment.Treatment typically is administered from one to three times daily.

“Halo” or “halogen” means chloro, bromo, fluoro, or iodo. In oneembodiment, halo is fluoro.

“Alkyl” means a straight or branched hydrocarbon group having 1 to 15carbon atoms in the chain. In one embodiment, alkyl groups have 1 to 12carbon atoms in the chain. In another embodiment, alkyl groups have 1 to6 carbon atoms. Exemplary alkyl groups include, but are not limited to,methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl,n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl, and dodecyl.

“Alkoxy” is an alkyl group which is attached to another moiety via anoxygen linker (—O(alkyl)). Non-limiting examples include methoxy,ethoxy, propoxy, and butoxy.

“Haloalkyl” or “halogenated alkyl” means an alkyl group in which one ormore, including all, of the hydrogen radicals are replaced by a halogroup, wherein each halo group is independently selected from —F, —Cl,—Br, and —I. For example, the term “halomethyl” or “halogenated methyl”means a methyl in which one to three hydrogen radical(s) have beenreplaced by a halo group. Representative haloalkyl groups includefluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl,1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like. Otherexamples include groups such as but are not limited to —CH₂CF₃,—CH(CH₂F)₂, —CH(CHF₂)₂, —CH(CF₃)₂, —CF(CH₃)₂, —CF₃.

“Haloalkoxy” is a haloalkyl group which is attached to another moietyvia an oxygen linker such as but are not limited to —OCHCF₂ or —OCF₃.

“Alkoxyalkyl” is an alkoxy group which is attached to another moiety viaan alkyl linker.

“Hydroxyalkyl” or “dihydroxyalkyl” is one or two hydroxy groups,respectively, which are attached to another moiety via an alkyl linker.Representative “hydroxyalkyl” or “dihydroxyalkyl” include —CH₂OH,—CH(OH)(CH₂)(OH), —C(OH)(CH₃)₂, —CH(OH)(CH₃), —CH(OH)(CH₂)(CH₃),—CH(OH)(CH₂)₂(CH₃), —C(CH₃)₂(OH), and the like.

“Cycloalkyl” means a non-aromatic monocyclic ring system of 3 to 10carbon atoms. In one embodiment, the cycloalkyl group has 3 to 6 carbonatoms. Exemplary cycloalkyl rings include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

“Cycloalkoxy” means a cycloalkyl group which is attached to anothermoiety via an oxygen linker (—O(cycloalkyl)).

“Monocyclic non-aromatic heterocycle” means a single saturatedheterocyclic ring, typically having 3- to 10-members and more typically3 to 7-members in the ring, wherein at least one atom in the ring is aheteroatom such as, for example, nitrogen, oxygen, sulfur, includingsulfoxide and sulfone. A 3- to 4-membered monocyclic non-aromaticheterocycle can contain up to 2 heteroatoms; a 5-6 membered monocyclicheterocycle can contain up to 3 heteroatoms and a 7- to 10-memberedmonocyclic non-aromatic heterocycle can contain up to 4 heteroatoms. Themonocyclic non-aromatic heterocycle may be attached to another group viaany heteroatom or carbon atom of the monocyclic non-aromaticheterocycle. Representative monocyclic non-aromatic heterocycles includemorpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,piperazinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,isothiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like. In one embodiment, a monocyclic non-aromatic heterocycle is aheterocyclic ring of 4, 5, 6, or 7 members.

“Monocyclic heteroaromatic” comprises carbon atom ring members and oneor more heteroatom ring members. Each heteroatom is independentlyselected from nitrogen, oxygen, and sulfur, including sulfoxide andsulfone. The point of attachment of a monocyclic heteroaromatic ring toanother group may be at either a carbon atom or a heteroatom of theheteroaromatic. In one embodiment, the monocyclic heteroaromatic ring isselected from 5 to 8 membered monocyclic heteroaromatic rings.Representative monocyclic heteroaromatic groups include pyridyl,1-oxo-pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl,thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, a triazinyl, triazolyl, thiadiazolyl, andtetrazolyl.

A protecting group is a group which is bonded to a reactive functionalgroup in a compound to convert the reactive functional group to another,non-reactive group to allow, for example, reaction(s) at another part ofthe molecule without interference from the reactive functional group.Once the reaction(s) at the other part of the molecule have beencompleted, the protecting groups is removed to regenerate the originalreactive functional group. Protecting groups for an hydroxy group (—OH)and reactions and conditions for protecting and deprotecting the hydroxygroup are well known in the art and are disclosed, for example, inGreene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley &Sons (2007), Chapter 2 and references cited therein. For example, aprotecting group may protect a hydroxy group as an ether. Suchprotecting groups include, but are not limited to methyl, methoxymethyl,methylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl,p-methoxybenzyloxymethyl, [3,4-dimethoxybenzyl)oxy]methyl,p-nitrobenzyloxymethyl, o-nitrobenzyloxymethyl,[(R)-1-(2-nitrophenyl)ethoxy]methyl, (4-methoxyphenoxy)methyl,guaiacolmethyl, [(p-phenylphenyl)oxy]methyl, t-butoxymethyl,4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl,2-cyanoethoxymethyl, bis(2-chloroethoxy)methyl,2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl,menthoxymethyl, O-bis(2-acetoxyethoxy)methyl, tetrahydropyranyl,fluorous tetrahydropyranyl, 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl,S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1-(2-fluorophenyl)-4-methoxypiperidin-4-yl,1-(4-chlorophenyl)-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl,tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahyrdo-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxyl)ethyl, 2-hydroxyethyl, 2-bromoethyl,1-[2-(trimethylsilyl)ethoxy]ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,1-methyl-1-phenoxyethyl, 2,2,2-trichloroethyl,1,1,-dianisyl-2,2,2,-trichloroethyl,1,1,1,3,3,3-hexafluoro-2-phenylisopropyl, 1-(2-cyanoethoxyl)ethyl,2-trimethylsilylethyl, 2-(benzylthio)ethyl, 2-(phenylselenyl)ethyl,t-butyl, cyclohexyl, 1-methyl-1′-cyclopropylmethyl, allyl, prenyl,cinnamyl, 2-phenallyl, propargyl, p-chlorophenyl, p-methoxyphenyl,p-nitrophenyl, 2,4-dinitrophenyl,2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl, benzyl, p-methoxybenzyl,3,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl,pentadienylnitrobenzyl, pentadienylnitropiperonyl, halobenzyl,2,6-dichlorobenzyl, 2,4-dichlorobenzyl, 2,6-difluorobenzyl,p-cyanobenzyl, fluoros benzyl, 4-fluorousalkoxybenzyl,trimethylsilylxylyl, p-phenylbenzyl, 2-phenyl-2-propyl(cumyl),p-acylaminobenzyl, p-azidobenzyl, 4-azido-3-chlorobenzyl, 2- and4-trifluoromethylbenzyl, p-(methylsulfinyl)benzyl, p-siletanylbenzyl,4-acetoxybenzyl, 4-(2-trimethylsilyl)ethoxymethoxybenzyl,2-naphthylmethyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido,2-quinolinylmethyl, 6-methoxy-2-(4-methylpheny)-4-quinolinemethyl,1-pyrenylmethyl, diphenylmethyl, 4-methoxydiphenylmethyl,4-phenyldiphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, tris(4-t-butylphenyl)methyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl,4-(4′-bromophenacyloxyl)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″tris(benzoyloxyphenyl)methyl,4,4′-dimethoxy-3″-[N-(imidazolylmethyl)trityl,4,4′-dimethoxy-3″-[N-(imidazolylethyl)carbamoyl]trityl,bis(4-methoxyphenyl)-1′-pyrenylmethyl,4-(17-tetrabenzo[a,c,g,i]fluorenylmethyl)-4,4″-dimethoxytrityl,9-anthryl, 9-(9-phenyl)xanthenyl, 9-phenylthioxanthyl,9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl,4,5-bis(ethoxycarbonyl[1,3]-dioxolan-2-yl, benzisothiazolyl S,S-dioxido,trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsiyl,diethylisopropylsilyl, dimethylthexylsilyl, 2-norbornyldimethylsily,t-butyldimethylsilyl, t-butyldiphenylsilyl (TBDPS), tribenzylsilyl,tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,di-t-butylmethylsilyl, bis(t-butyl)-1-pyrenylmethoxysilyl,tris(trimethylsilyl)silyl, sisyl, (2-hydroxystyryl)dimethylsilyl,(2-hydroxystyryl)diisopropylsily, t-butylmethoxyphenylsilyl,t-butoxydiphenylsilyl,1,1,3,3-tetraisopropyl-3-[2-(triphenylmethoxy)ethoxy]disiloxane-1-yl,fluorous silyl.

Alternatively, suitable protecting groups protect the hydroxy group asesters, for example, formate, benzoylformate, acetate, chloroacetate,dichloroacetate, trichloroacetate, trichloroacetamidate,trifluoroacetate, methoxyacetate, triphenylmethoxyacetate,phenoxyacetate, p-chlorophenoxyacetate, phenylacetate,p-P-phenylacetate, diphenylacetate, 3-phenylpropionate, bisfluorouschain type propanoyl (Bfp-OR), 4-pentenoate, 4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate,5-[3-Bis(4-methoxyphenyl)hydroxymethylphenoxy]levulinate, pivaloate,1-adamantoate, crotonate, 4-methoxycrotonate, benzoate,p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), 4-bromobenzoate,2,5-difluorobenzoate, p-nitrobenzoate, picolinate, nicotinate,2-(azidomethyl)benzoate, 4-azidobutyrate, (2-azidomethyl)phenylacetate,2-{[(tritylthio)oxy]methyl}benzoate,2-{[(4-methoxytritylthio)oxy]methyl}benzoate,2-{[methyl(tritylthio)amino]methyl}benzoate,2{{[4-methoxytrityl)thio]methylamino}-methyl}benzoate,2-(allyloxy)phenylacetate, 2-(prenyloxymethyl)benzoate,6-(levulinyloxymethyl)-3-methoxy-2- and 4-nitrobenzoate,4-benzyloxybutyrate, 4-trialkylsiloxybutrate,4-acetoxy-2,2-dimethylbutyrate, 2,2-dimethyl-4-pentenoate,2-iodobenzoate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 4-methylthiomethoxy)butyrate,2-methylthiomethoxymethyl)benzoate, 2-(chloroacetoxymethyl)benzoate,2[(2-chloroacetoxy)ethyl]benzoate, 2-[2-(benzyloxy)ethyl]benzoate,2-[2-(4-methoxybenzyloxyl)ethyl]benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-imethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate tigloate),o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, 2-chlorobenzoate, assulfonates, sulfenates and sulfinates such as sulfate, allylsulfonate,ethanesulfonate (mesylate), benzylsulfonate, tosylate,2-[(4-nitrophenyl)ethyl]sulfonate, 2-trifluoromethylsulfonate,4-monomethoxytritylsulfenate, alkyl 2,4-initrophenylsulfenate,2,2,5,5-tetramethylpyrrolidin-3-one-1-sulfinate, borate,dimethylphosphinothioyl, as carbonates such as alkyl methyl carbonate,methoxymethyl carbonate, 9-fluorenylmethyl carbonate, ethyl carbonate,bromoethyl carbonate, 2-(methylthiomethoxy)ethyl carbonate,2,2,2-trichloroethyl carbonate, 1,1-dimethyl-2,2,2-trichloroethylcarbonate, 2-(trimethylsilyl)ethyl carbonate,2-[dimethyl(2-naphthylmethyl)silyl]ethyl carbonate,2-(phenylsulfonyl)ethyl carbonate, 2-(triphenylphosphonio)ethylcarbonate, cis-[4-[[(-methoxytrityl)sulfenyl]oxy]tetraydrofuran-3-yl]oxycarbonate, isobutyl carbonate, t-butyl carbonate, vinyl carbonate, allylcarbonate, cinnamyl carbonate, propargyl carbonate, p-chlorophenylcarbonate, p-nitrophenyl carbonate, 4-ethoxyl-1-naphthyl carbonate,6-bromo-7-hydroxycoumarin-4-ylmethyl carbonate, benzyl carbonate,o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, p-methoxybenzylcarbonate, 3,4-dimethoxybenzyl carbonate, anthraquinon-2-ylmethylcarbonate, 2-dansylethyl carbonate, 2-(4-nitrophenyl)ethyl,2-(2,4-nitrophenyl)ethyl, 2-(2-nitrophenyl)propyl,2-(3,4-methylenedioxy-6-nitrophenylpropyl, 2-cyano-1-phenylethylcarbonate, 2-(2-pyridyl)amino-1-phenylethyl carbonate,2-[N-methyl-N-(2-pyridyl)]amino-1-phenylethyl carbonate, phenacylcarbonate, 3′,5′-dimethoxybenzoin carbonate, methyl dithiocarbonate,S-benzyl thiocarbonate, and carbamates such as dimethylthiocarbamate,N-phenylcarbamate, and N-methyl-N-(o-nitrophenyl)carbamate.

C. Pharmaceutical Compositions, Formulations and Dosages

In one embodiment, provided herein is a pharmaceutical compositioncomprising a compound of the invention and a pharmaceutically acceptablecarrier or diluent.

In the pharmaceutical compositions of the invention, the compound of theinvention is present in an effective amount. The interrelationship ofdosages for animals and humans (based on milligrams per meter squared ofbody surface) is described in Freireich et al., Cancer Chemother. Rep,1966, 50: 219. Body surface area may be determined approximately fromheight and weight of the patient. See, e.g., Scientific Tables, GeigyPharmaceuticals, Ardsley, N.Y., 1970, 537.

The LXR modulators herein (e.g., compound(s) of the invention) can beformulated as pharmaceutical compositions and administered to a subject,such as a human, in a variety of forms adapted to the chosen route ofadministration. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, buccal,transdermal, inhalation, parenteral, sublingual, rectal, vaginal, andintranasal. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrathecal, intrasternalinjection or infusion techniques. Methods of formulating pharmaceuticalcompositions are well known in the art, for example, as disclosed in“Remington: The Science and Practice of Pharmacy,” University of theSciences in Philadelphia, ed., 21st edition, 2005, Lippincott, Williams& Wilkins, Philadelphia, Pa. Each of the LXR modulators may be usedalone or in combination as a part of a pharmaceutical composition of theinvention.

The pharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Thus, the present compounds may be systemically administered,e.g., orally, in combination with a pharmaceutically acceptableexcipient such as an inert diluent or an assimilable edible carrier.They may be enclosed in hard or soft shell gelatin capsules, may becompressed into tablets or may be incorporated directly with the food ofthe patient's diet. For oral therapeutic administration, the activecompound may be combined with one or more excipients and used in theform of ingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like.

Suitable tablets may be obtained, for example, by mixing one or morecompounds of the invention with known excipients, for example inertdiluents, carriers, disintegrants, adjuvants, surfactants, bindersand/or lubricants. The tablets may also consist of several layers.

The compounds of the invention can be suitably formulated intopharmaceutical compositions for administration to a subject. Thepharmaceutical compositions of the invention optionally include one ormore pharmaceutically acceptable carriers and/or diluents therefor, suchas lactose, starch, cellulose and dextrose. Other excipients, such asflavoring agents; sweeteners; and preservatives, such as methyl, ethyl,propyl and butyl parabens, can also be included. More complete listingsof suitable excipients can be found in the Handbook of PharmaceuticalExcipients (5th Ed., Pharmaceutical Press (2005)). A person skilled inthe art would know how to prepare formulations suitable for varioustypes of administration routes. Conventional procedures and ingredientsfor the selection and preparation of suitable formulations aredescribed, for example, in Remington's Pharmaceutical Sciences(2003—20th edition) and in The United States Pharmacopeia: The NationalFormulary (USP 24 NF19) published in 1999. The carriers, diluents and/orexcipients are “acceptable” in the sense of being compatible with theother ingredients of the pharmaceutical composition and not deleteriousto the recipient thereof.

Typically, for oral therapeutic administration, a compound of theinvention may be incorporated with excipient and used in the form ofingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like.

Typically for parenteral administration, solutions of a compound of theinvention can generally be prepared in water suitably mixed with asurfactant such as hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, DMSO and mixturesthereof with or without alcohol, and in oils. Under ordinary conditionsof storage and use, these preparations contain a preservative to preventthe growth of microorganisms.

Typically, for injectable use, sterile aqueous solutions or dispersionof, and sterile powders of, a compound of the invention for theextemporaneous preparation of sterile injectable solutions ordispersions.

For nasal administration, the compounds of the invention can beformulated as aerosols, drops, gels and powders. Aerosol formulationstypically comprise a solution or fine suspension of the active substancein a physiologically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomizing device. Alternatively, the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal after use. Where the dosage form comprises an aerosoldispenser, it will contain a propellant which can be a compressed gassuch as compressed air or an organic propellant such asfluorochlorohydrocarbon. The aerosol dosage forms can also take the formof a pump-atomizer.

For buccal or sublingual administration, the compounds of the inventioncan be formulated with a carrier such as sugar, acacia, tragacanth, orgelatin and glycerine, as tablets, lozenges or pastilles.

For rectal administration, the compounds of the invention can beformulated in the form of suppositories containing a conventionalsuppository base such as cocoa butter.

Topical and/or local administration of the compounds of the inventioncan be achieved in a variety of ways including but not limited toointments, lotions, pastes, creams, gels, powders, drops, sprays,solutions, inhalants, patches, suppositories, retention enemas, chewableor suckable tablets or pellets and aerosols. Topical and/or localadministration may also involve the use of transdermal administrationsuch as transdermal patches or iontophoresis devices. For topical and/orlocal administration, the compounds of the invention can be formulatedas ointments, creams, milks, salves, powders, impregnated pads, syndets,solutions, gels, sprays, foams, suspensions, lotions, sticks, shampoosor washing bases. Compounds of the invention may also be administered inthe form of suspensions of lipid or polymer vesicles or nanospheres ormicrospheres or polymer patches and hydrogels for controlled release.

D. Methods of Treatment and Use of the LXR Modulators

Provided herein is a method of treating a subject with a disease ordisorder that is treatable by modulation of LXR. In one embodiment, LXRis modulated by upregulating LXR activity. The method comprisesadministering an effective amount of the compound of the invention.Moreover, provided herein is the use of a compound of the invention forthe manufacture of a medicament for treating a subject with a disease ordisorder that is treatable by upregulating LXR activity in a subject inneed thereof.

The methods provided herein may be useful for disorders treatable withLXR modulation, in particular LXR agonism.

Compounds of the invention are useful for the treatment or prevention ofdiseases or disorders associated with altered cholesterol transport,reverse cholesterol transport, fatty acid metabolism, cholesterolabsorption, cholesterol re-absorption, cholesterol secretion,cholesterol excretion, or cholesterol metabolism. Representativediseases or disorders include, but are not limited to, a lipid disorder;cancer, particularly hormone-dependent cancers, including ovarian,breast and prostate cancer; acneiform skin condition; skin inflammatorydisease; immunological disorder; condition characterized by a perturbedepidermal barrier function; condition of disturbed differentiation orexcess proliferation of the epidermis or mucous membrane; cardiovasculardisease; reproductive tract disorders; optic nerve and retinalpathology; degenerative neuropathy occurring in a disease; autoimmunedisease; traumatic damage to the central or peripheral nervous system;neurodegenerative disease; or a degenerative process due to aging;diseases or disorders of the kidney; and osteoporosis and relateddiseases.

In another embodiment, the disease or disorder is hyperlipidemia,hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia,lipodystrophy, hepatic steatosis, nonalcoholic steatohepatitis (NASH),nonalcoholic fatty liver disease (NAFLD), hyperglycemia, insulinresistance, diabetes mellitus, dyslipidemia, atherosclerosis, gallstonedisease, acne vulgaris, dermatitis (including but not limited to,psoriasis, contact dermatitis, atopic dermatitis, and eczema), skinwounds, skin aging, photoaging, wrinkling, diabetes, Niemann-Pickdisease type C, Parkinson's disease, Alzheimer's disease, inflammation,xanthoma, obesity, metabolic syndrome, syndrome X, stroke, peripheralocclusive disease, memory loss, diabetic neuropathies, proteinuria,glomerulopathies (including but not limited to, diabetic nephropathy,hypertensive nephropathy, IGA nephropathy, focal segmentalglomerulosclerosis), hyperphosphatemia, associated cardiovascularcomplications of hyperphosphatemia, cancer, multiple sclerosis orosteoporosis.

In another embodiment, the disease or disorder is common acne;comedones; polymorphs; rosacea; nodulocystic acne; acne conglobate;senile acne; secondary acne, including but not limited to solar,medicinal and occupational acne; ichthyosis; ichthyosiform conditions;Darier's disease; palmoplantar keratoderma; leukoplakia; leukoplakiformconditions; cutaneous or mucous (oral) lichen; dermatological conditionsor afflictions with an inflammatory immunoallergic component, with orwithout a cellular proliferation disorder, including but not limited tocutaneous psoriasis, mucous psoriasis, ungual psoriasis, psoriaticrheumatism, cutaneous atopy, including eczema, respiratory atopy andgingival hypertrophy; benign or malignant dermal or epidermalproliferations, of viral or non-viral origin, including but not limitedto common warts, flat warts, epidermodysplasia verruciformis, oral orflorid papillomatoses, and T lymphoma or cutaneous T-cell lymphoma;proliferations that may be induced by ultraviolet light, including butnot limited to basocellular epithelioma and spinocellular epithelioma;precancerous skin lesions, including but not limited tokeratoacanthomas; immune dermatitides, including but not limited tolupus erythematosus; bullous immune diseases; collagen diseases,including but not limited to scleroderma; dermatological or systemicconditions or afflictions with an immunological component; skindisorders due to exposure to UV radiation; photo-induced orchronological aging of the skin; actinic pigmentations; keratosis;pathology associated with chronological or actinic aging, including butnot limited to xerosis; sebaceous function disorders, including but notlimited to hyperseborrhoea of acne, simple seborrhoea and seborrhoeicdermatitis; cicatrization disorders, including but not limited tostretch marks; pigmentation disorders, including but not limited tohyperpigmentation, melasma, hypopigmentation, and vitiligo; andalopecia, including but not limited to chemotherapy-associated alopeciaand radiation-associated alopecia.

In an embodiment, the disease or disorder is hypercholesterolemia,atherosclerosis or dyslipidemia. In another embodiment, the disease ordisorder is atherosclerosis or dyslipidemia. In yet another embodiment,the disease or disorder is atherosclerosis, Alzheimer's disease ordermatitis.

The present invention also provides a method for increasing reversecholesterol transport and/or for inhibiting the progression of orpromoting the regression of atherosclerosis.

The present invention also provides a method of treating diseases ordisorders associated with a need for increasing high density lipoprotein(HDL)-cholesterol levels comprising the administration of an effectiveamount of a compound of the invention to a mammal (particularly a human)in need thereof.

The present invention also provides a method of treating a disease ordisorder associated with a need for decreasing low density lipoprotein(LDL)-cholesterol levels comprising the administration of an effectiveamount of a compound of the invention to a mammal (particularly a human)in need thereof.

Additionally, provided herein is a method of increasing the expressionof an ATP-Binding Cassette protein in a subject's cells, therebyincreasing reverse cholesterol transport in a subject using thecompounds of the invention and compositions provided herein.

Standard physiological, pharmacological and biochemical procedures areknown to the art and are available for evaluating compounds of thepresent invention for the ability to modulate LXR activity. Such assaysinclude, for example, binding assays, fluorescence polarization assays,FRET based co-activator recruitment assays, and cell-basedco-transfection assays. Compounds of the present invention can beevaluated for their ability to modulate the expression of genes known tobe modulated by LXR. Established animal models can be used to study theprofiles of compounds of the present invention in relation to parametersdirectly relevant to diseases or disorders, including atherosclerosis,Alzheimer's disease, and skin conditions. Thus, compounds of the presentinvention can be tested in vivo in animal models by a variety of routesof administration, for example, oral gavage. Typically, in vivo compoundexposure can be examined in plasma and in tissues of interest. LXRactivity (as detected by gene expression of LXR-responsive genes) can beexamined in whole blood and tissues of interest. Lipids can bequantified in the plasma and the liver.

In particular, compounds of the present invention can be tested fortheir activity on ATP-Binding Cassette (ABC) cholesterol transporters,such as ABCA1 and ABCG1, and on lipogenic markers, such as SREBP1c atthe gene and protein expression level. The functional consequences ofABC transporter induction can be examined in cellular models forcholesterol efflux and in animal models for the reverse cholesterolpathway and atherosclerosis. Lipogenic markers can be examined in animalmodels by measuring plasma and liver triglyceride levels.

The compounds of the present invention can be used alone (i.e., as amonotherapy) or in combination with one or more other therapeutic agenteffective for treating any of the above indications. The pharmaceuticalcompositions can comprise the disclosed compounds alone as the onlypharmaceutically active agent or can comprise one or more additionalpharmaceutically active agents.

The present invention also provides combination therapy for treating orameliorating a disease or a disorder described herein. In someembodiments, the combination therapy comprises administering at leastone compound represented by Structural Formula I, II, III, IV, V, or VIin combination with one or more agents for treating or ameliorating adisease or a disorder described herein. In some embodiments, thecombination therapy comprises administering at least one compoundrepresented by Structural Formula I, II, III, IV, V, or VI incombination with one or more agents for the treatment of diseasesincluding hyperlipidemia, hypercholesterolemia, hyperlipoproteinemia,hypertriglyceridemia, lipodystrophy, hepatic steatosis, NASH, NAFLD,hyperglycemia, insulin resistance, diabetes mellitus, dyslipidemia,atherosclerosis, gallstone disease, acne vulgaris, dermatitis (includingbut not limited to, psoriasis, contact dermatitis, atopic dermatitis,and eczema), skin wounds, skin aging, photoaging, wrinkling, diabetes,Niemann-Pick disease type C, Parkinson's disease, Alzheimer's disease,inflammation, xanthoma, obesity, metabolic syndrome, syndrome X, stroke,peripheral occlusive disease, memory loss, diabetic neuropathies,proteinuria, glomerulopathies (including but not limited to, diabeticnephropathy, hypertensive nephropathy, IGA nephropathy, focal segmentalglomerulosclerosis), hyperphosphatemia, associated cardiovascularcomplications of hyperphosphatemia, cancer, multiple sclerosis orosteoporosis.

In some embodiments, the compounds of the invention are used incombination with one or more additional agents for the treatment ofdiabetes, dyslipidemia, cardiovascular disease, hypertension, orobesity. Agents for the treatment of diabetes include insulins, such asHumulin® (Eli Lilly), Lantus® (Sanofi Aventis), Novolin® (Novo Nordisk),and Exubera® (Pfizer); PPAR gamma agonists, such as Avandia®(rosiglitizone maleate, GSK) and Actos® (pioglitazone hydrochloride,Takeda/Eli Lilly); sulfonylureas, such as Amaryl® (glimepiride, SanofiAventis), Diabeta® (glyburide, Sanofi Aventis), Micronase®/Glynase®(glyburide, Pfizer), and Glucotrol®/Glucotrol XL® and (glipizide,Pfizer); meglitinides, such as Prandin®/NovoNorm® (repaglinide, NovoNordisk), Starlix® (nateglinide, Novartis), and Glufast® (mitiglinide,Takeda); biguanides, such as Glucophage/Glucophage XR® (metformin HCl,Bristol Myers Squibb) and Glumetza® (metformin HCl extended releasetablets, Depomed); thiazolidinediones; amylin analogs, GLP-1 analogs oragonists (including Byetta® (exenatide, Amylin/Eli Lilly) and Victoza®(recombinant liraglutide, Novo Nordisk)); DPP-IV inhibitors includingTradjenta™ (Eli Lilly/Boehringer Ingelheim), Januvia® (Merck), Galvus®(Novartis), and Onglyza® (Bristol-Myers Squibb/AstraZeneca); PTB-1 Binhibitors; protein kinase inhibitors (including AMP-activated proteinkinase inhibitors); glucagon antagonists, glycogen synthase kinase-3beta inhibitors; glucose-6-phoshatase inhibitors; glycogen phosphorylaseinhibitors; sodium glucose co-transporter inhibitors, andalpha-glucosidase inhibitors, such asPrecose®/Glucobay®/Prandase®/Glucor® (acarbose, Bayer) and Glyset®(miglitol, Pfizer). Agents for the treatment of dyslipidemia andcardiovascular disease include statins, fibrates, and ezetimbe. Agentsfor the treatment of hypertension include alpha-blockers, beta-blockers,calcium channel blockers, diuretics, angiotensin converting enzyme (ACE)inhibitors, dual ACE and neutral endopeptidase (NEP) inhibitors,angiotensin-receptor blockers (ARBs), aldosterone synthase inhibitors,aldosterone-receptor antagonists, or endothelin receptor antagonists.Agents for the treatment of obesity include orlistat, phentermine,sibutramine and rimonabant.

An embodiment of the invention includes administering an LXR modulatorcompound of the invention or composition thereof in a combinationtherapy with combination products, such as Avandamet® (metformin HCl androsiglitazone maleate, GSK); Avandaryl® (glimepiride and rosiglitazonemaleate, GSK); Metaglip® (glipizide and metformin HCl, Bristol MyersSquibb); and Glucovance® (glyburide and metformin HCl, Bristol MyersSquibb).

In some embodiments, the combination therapy comprises administering atleast one compound of the invention in combination with one or morecompound selected from the group of, for example, beta secretase (BACE1)inhibitors; gamma-secretase inhibitors; amyloid aggregation inhibitors(e.g., ELND-005); directly or indirectly acting neuroprotective and/ordisease-modifying substances; anti-oxidants (e.g., vitamin E orginkolide); anti-inflammatory substances (e.g., Cox inhibitors, NSAIDs);HMG-CoA reductase inhibitors (statins); acetylcholinesterase inhibitors(e.g., donepezil, rivastigmine, tacrine, galantamine, memantine;tacrine); NMDA receptor antagonists (e.g., memantine); AMPA receptoragonists; AMPA receptor positive modulators, AMPAkines, monoaminereceptor reuptake inhibitors, substances modulating the concentration orrelease of neurotransmitters; substances inducing the secretion ofgrowth hormone (e.g., ibutamoren mesylate and capromorelin); CB-1receptor antagonists or inverse agonists; antibiotics (e.g., minocyclinor rifampicin); PDE2, PDE4, PDE5, PDE9, PDE10 inhibitors, GABAA receptorinverse agonists, GABAA receptor antagonists, nicotinic receptoragonists or partial agonists or positive modulators, alpha4beta2nicotinic receptor agonists or partial agonists or positive modulators,alpha7 nicotinic receptor agonists or partial agonists or positivemodulators; histamine H3 antagonists, 5 HT-4 agonists or partialagonists, 5HT-6 antagonists, alpha2-adrenoreceptor antagonists, calciumantagonists, muscarinic receptor M1 agonists or partial agonists orpositive modulators, muscarinic receptor M2 antagonists, muscarinicreceptor M4 antagonists, metabotropic glutamate-receptor 5 positivemodulators, antidepressants, such as citalopram, fluoxetine, paroxetine,sertraline and trazodone; anxiolytics, such as lorazepam and oxazepam;antiphychotics, such as aripiprazole, clozapine, haloperidol,olanzapine, quetiapine, risperidone and ziprasidone, and othersubstances that modulate receptors or enzymes in a manner such that theefficacy and/or safety of the compounds according to the invention isincreased and/or unwanted side effects are reduced. The compoundsaccording to the invention may also be used in combination withimmunotherapies for the treatment of a disease or disorder disclosedherein.

Combination therapy includes co-administration of a compound of theinvention and one or more other agent, sequential administration of acompound of the invention and one or more other agent, administration ofa composition containing a compound of the invention and one or moreother agent, or simultaneous administration of separate compositionscontaining a compound of the invention and one or more other agent.

E. Exemplary Synthesis General Description of Synthetic Methods

The compounds of the present invention can be readily prepared accordingto the following reaction schemes and examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. Many of the reactions can also becarried out under microwave conditions or using conventional heating orutilizing other technologies such as solid phase reagents/scavengers orflow chemistry. In these reactions, it is also possible to make use ofvariants which are themselves known to those of ordinary skill in thisart, but are not mentioned in greater detail. Furthermore, other methodsfor preparing compounds of the invention will be readily apparent to aperson of ordinary skill in the art in light of the following reactionschemes and examples. In cases where synthetic intermediates and finalproducts contain potentially reactive functional groups, for exampleamino, hydroxy, thiol and carboxylic acid groups, that may interferewith the desired reaction, it may be advantageous to employ protectedforms of the intermediate. Methods for the selection, introduction andsubsequent removal of protecting groups are well known to those skilledin the art. In the discussion below X, R¹, R², R³, R⁴, R⁵ and R⁶ havethe meanings indicated above unless otherwise indicated. Theabbreviations used in these experimental details are listed below andadditional ones should be known to a person skilled in the art ofsynthesis. In addition one can refer to the following references forsuitable methods of synthesis as described in March, Advanced OrganicChemistry, 3rd edition, John Wiley & Sons, 1985, Greene and Wuts,Protective Groups in Organic Synthesis, 2^(nd) edition, John Wiley &Sons, 1991, and Richard Larock, Comprehensive Organic Transformations,4^(th) edition, VCH publishers Inc., 1989.

Generally, reagents in the reaction schemes are used in equimolaramounts; however, in certain cases it may be desirable to use an excessof one reagent to drive a reaction to completion. This is especially thecase when the excess reagent can be readily removed by evaporation orextraction. Bases employed to neutralize HCl in reaction mixtures aregenerally used in slight to substantial excess (1.05-5 equivalents).

Where NMR data are presented, spectra were obtained on a Varian 400 (400MHz) or 300 (300 MHz) and are reported as ppm downfield fromtetramethylsilane with number of proton, multiplicities and couplingconstants indicated parenthetically along with reference to deuteratedsolvent.

LC-MS data were obtained by utilizing the following chromatographicconditions:

Method 1 (10-80, 2 min)

Column Xtimate ™ C18 2.1 * 30 mm, 3 μm A: water (4 L) + TFA (1.5 mL) B:acetonitrile (4 L) + TFA (0.75 mL) TIME (min) A % B % Mobile Phase 0 9010 0.9 20 80 1.5 20 80 1.51 90 10 2 90 10 Flow Rate 1.2 mL/minwavelength UV 220 nm Oven Temp 50° C. MS ionization ESIMethod 2 (30-90, 2 min)

Column Xtimate ™ C18 2.1 * 30 mm, 3 μm A: water (4 L) + TFA (1.5 mL) B:acetonitrile (4 L) + TFA (0.75 mL) TIME (min) A % B % Mobile Phase 0 7030 0.9 10 90 1.5 10 90 1.51 70 30 2 70 30 Flow Rate 1.2 mL/minwavelength UV 220 nm Oven Temp 50° C. MS ionization ESIMethod 3 (0-60, 2 min)

Column Xtimate ™ C18 2.1 * 30 mm, 3 μm A: water (4 L) + TFA (1.5 mL) B:acetonitrile (4 L) + TFA (0.75 mL) TIME (min) A % B % Mobile Phase 0 1000 0.9 40 60 1.5 40 60 1.51 100 0 2 100 0 Flow Rate 1.2 mL/min wavelengthUV 220 nm Oven Temp 50° C. MS ionization ESIMethod 4:

-   -   HPLC System: Waters ACQUITY; Column: Waters ACQUITY CSH™ C18 1.7        μM    -   Guard column: Waters Assy. Frit, 0.2 μM, 2.1 mm; Column tem: 40°        C.    -   Mobile Phase: A: TFA: Water (1:1000, v:v) Mobile phase B: TFA:        ACN (1:1000, v:v);    -   Flow Rate: 0.65 mL/min; Injection Volume: 2 μL; Acquisition        time: approximately 1.5 minute.

Gradient Program: Time (min) B % 0 10 0.8 90 1.20 90 1.21 10Mass Spectrometer Parameters

Mass Spectrometer: Waters SQD; Ionization: Positive ElectrosprayIonization (ESI); Mode Scan (100-1400 m/z in every 0.2 second); ESCapillary Voltage: 3.5 kv; ES Cone Voltage: 25 v Source Temperature:120° C.; Disolvation Temperature: 500° C.; Desolvation Gas Flow:Nitrogen Setting 650 (L/hr); Cone Gas Flow: Nitrogen Setting 50 (L/hr)

SFC separation of compounds of the invention were carried out under thefollowing methods.

Method A:

-   -   Instrument: Thar SFC 80; Column: AD 250 mm*30 mm, 5 μm; Mobile        phase: A: Supercritical CO₂, B: IPA (0.05% DEA), A: B=80:20 at        60 ml/min; Column Temp: 38° C.; Nozzle Pressure: 100 Bar; Nozzle        Temp: 60° C.; Evaporator Temp: 20° C.; Trimmer Temp: 25° C.;        Wavelength: 220 nm.

Method B:

-   -   Instrument: SFC MG2; Column: OJ 250 mm*30 mm, 5 μm; Mobile        phase: A: Supercritical CO₂, B: MeOH (0.05% DEA), A:B=90:10 at        70 ml/min; Column Temp: 38° C.; Nozzle Pressure: 100 Bar Nozzle        Temp: 60° C.; Evaporator Temp: 20° C.; Trimmer Temp: 25° C.;        Wavelength: 220 nm        Analytical Chiral HPLC

The chiral purity of compounds of the invention was determined byanalytical chiral HPLC, which was carried out using Chiralcel® orChiralpak® columns, using CO₂, together with from 5% to 40% methanol,ethanol or isopropanol, containing 0.05% DEA, as eluents.

Method Detailed information OJ-H_3_5_40_2.35 ML Column: Chiralcel ® OJ-H250 × 4.6 mm I.D., 5 μm Mobile phase: methanol (0.05% DEA) in CO₂ from5% to 40% Flow rate: 2.35 mL/min Wavelength: 220 nm OJ-H_3_5_40_2.5 MLColumn: Chiralcel ® OJ-H 250 × 4.6 mm I.D., 5 μm Mobile phase: methanol(0.05% DEA) in CO₂ from 5% to 40% Flow rate: 2.5 mL/min Wavelength: 220nm AS-H_3_5_40_2.35 ML Column: Chiralpak ® AS-H 250 × 4.6 mm I.D., 5 μmMobile phase: methanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 2.35mL/min Wavelength: 220 nm AS-H_4_5_40_2.5 ML Column: Chiralpak ® AS-H250 × 4.6 mm I.D., 5 μm Mobile phase: iso-propanol (0.05% DEA) in CO2from 5% to 40% Flow rate: 2.5 mL/min Wavelength: 220 nm AS-H_5_5_40_2.35ML Column: Chiralpak ® AS-H 250 × 4.6 mm I.D., 5 μm Mobile phase:ethanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 2.35 mL/minWavelength: 220 nm AS-H_3_5_40_2.5 ML Column: Chiralpak ® AS-H 250 × 4.6mm I.D., 5 μm Mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40%Flow rate: 2.5 mL/min Wavelength: 220 nm AD-H_3_5_40_2.35 ML Column:Chiralpak ® AD-H 250 × 4.6 mm I.D., 5 μm Mobile phase: methanol (0.05%DEA) in CO₂ from 5% to 40% Flow rate: 2.35 mL/min Wavelength: 220 nmAD-H_5_5_40_2.35 ML Column: Chiralpak ® AD-H 250 × 4.6 mm I.D., 5 μmMobile phase: ethanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 2.35mL/min Wavelength: 220 nm OD-3_3_5_40_2.5 ML Column: Chiralcel ® OD-3150 × 4.6 mm I.D., 3 μm Mobile phase: methanol (0.05% DEA) in CO₂ from5% to 40% Flow rate: 2.5 mL/min Wavelength: 220 nm OD-3_4_5_40_2.5 MLColumn: Chiralcel ® OD-3 150 × 4.6 mm I.D., 3 μm Mobile phase:iso-propanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 2.5 mL/minWavelength: 220 nm OD-3_5_5_40_2.5 ML Column: Chiralcel ® OD-3 150 × 4.6mm I.D., 3 μm Mobile phase: ethanol (0.05% DEA) in CO₂ from 5% to 40%Flow rate: 2.5 mL/min Wavelength: 220 nm AD-3_3_5_40_2.5 ML Column:Chiralpak ® AD-3 150 × 4.6 mm I.D., 3 μm Mobile phase: methanol (0.05%DEA) in CO₂ from 5% to 40% Flow rate: 2.5 mL/min Wavelength: 220 nmAD-3_4_5_40_2.5 ML Column: Chiralpak ® AD-3 150 × 4.6 mm I.D., 3 μmMobile phase: iso-propanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate:2.5 mL/min Wavelength: 220 nm AD-3_5_5_40_2.5 ML Column: Chiralpak ®AD-3 150 × 4.6 mm I.D., 3 μm Mobile phase: ethanol (0.05% DEA) in CO₂from 5% to 40% Flow rate: 2.5 mL/min Wavelength: 220 nm OD-H_3_5_40_2.35ML Column: Chiralcel ® OD-H 250 × 4.6 mm I.D., 5 μm Mobile phase:methanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 2.35 mL/minWavelength: 220 nm OD-H_5_5_40_2.35 ML Column: Chiralcel ® OD-H 250 ×4.6 mm I.D., 5 μm Mobile phase: ethanol (0.05% DEA) in CO₂ from 5% to40% Flow rate: 2.35 mL/min Wavelength: 220 nm

The invention is illustrated by way of the following examples, in whichthe following abbreviations may be employed:

Abbreviation Meaning ACN, MeCN, CH₃CN acetonitrile aq. aqueous Boctert-butoxy carbonyl or t-butoxy carbonyl brine saturated aqueous NaClCbz benzyloxy carbonyl CeCl₃ ceric chloride Cs₂CO₃ cesium carbonate CuIcuprous iodide DCM or CH₂Cl₂ methylene chloride DIEA diisopropyl ethylamine DMF dimethyl formamide DMS/Me2S dimethyl sulfide DMSO dimethylsulfoxide EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiiimidehydrochloride EtI ethyl iodide Et ethyl Et₂O ethyl ether Et₃SiHtriethylsilane Et₃N triethylamine EtOAc, EA, AcOEt ethyl acetate EtOHethanol FeCl₃ ferric chloride h, hr hour(s) HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate HBTUO-Benzotriazole-1-yl-N,N,N′,N′- tetramethyluronium-hexafluorophosphateHCl hydrochloric acid H₂O water H₂O₂ hydrogen peroxide HPLC highperformance liquid chromatography i-BuOCOCl iso-butoxycarbonyl chlorideICl iodochloride K₂CO₃ potassium carbonate K₃PO₄ tripotassium phosphateLC-MS liquid chromatography-mass spectrometry LDA lithiumdiiisopropylamide LiCl lithium chloride LiOH lithium hydroxide MCPBA,m-CPBA meta-chloroperoxybenzoic acid MeOH methanol MeI methyl iodide Memethyl mg milligram Mg₂SO₄ magnesium sulfate (anhydrous) min minute(s)mL milliliters mmol millimoles mp, m.p. melting point MS massspectrometry MW microwave NaBH₄ sodium borohydride NaBH₃CN sodiumcyanoborohydride NaH sodium hydride NaHCO₃ sodium bicarbonate NaOHsodium hydroxide NaOMe sodium methoxide Na₂S₂O₃ sodium thiosulfateNa₂S₂O₅ sodium dithionate Na₂SO₄ sodium sulfate NH₄OH ammonium hydroxide(NH₄)₂CO₃ ammonium carbonate NH₄Cl ammonium chloride Na₂CO₃ sodiumcarbonate NaHCO₃ sodium bicarbonate NaH sodium hydride n-BuLin-butyllithium NMM N-methyl-morpholine NMP N-methyl-pyrrolidin-2-one OTftrifluoromethanesulfonate OTs tosylate PdCl₂dppf[1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(ii) Pd₂(dba)3tris(dibenzylideneacetone)dipalladium(0) PE petroleum ether rt roomtemperature sat. saturated SFC supercritical fluid chromatography t-BuOKpotassium tert butoxide t-BuLi tert butyl lithium t-BuOOH tert butylperoxide TBAF tetrabutylammonium fluoride TFA trifluoroacetic acid THFtetrahydrofuran TLC thin layer chromatography Ti(OEt)₄ titanium tetraethoxide Zn zinc Zn(CN)₂ zinc cyanide

In the first process, a compound of Formula I can be prepared by S_(N)Aror palladium catalyzed reactions of reagents 1, where G¹ is Cl, Br, I,OTf or OTs, with intermediates of Formula 2. Reagents 1 are eithercommercially available or can be prepared readily from commerciallyavailable precursors based on literature precedents.

Intermediates 2 can be prepared by one of the several different methodsdepicted below.

When X=N, intermediates of Formula 2 can be prepared by cyclization ofintermediates of Formula 3a followed by removal of G² when G² is nothydrogen. G² is an amine protecting group, such as Boc, Cbz andtrifluoroacetamide, etc.

Intermediates of Formula 3a can be prepared by one of the twomethods: 1) copper mediated coupling of piperazinone 4a and aniline 5a,where G³ is Br, I, Cl or OTf; 2) S_(N)Ar reaction between 4a andfluorinated nitrobenzene 6a to give intermediate of Formula 7a followedby reduction of the nitro group. The intermediate 7a can also beprepared from an intermediate of Formula 8a by displacement of fluorinewith either sodium alkanesulfinate (R¹SO₂Na) or sodium alkylsulfide(R¹SNa) followed by oxidation of the resulting thioether. Theintermediate 8a in turn can be prepared from piperazinone 4a anddifluoro nitrobenzene 9a, which are either commercially available or canbe readily prepared from commercial precursors based on literatureprocedures, well known to those of ordinary skill in the art.

For example, when R³=isopropyl, piperazinone 4a can be prepared by oneof the methods presented below.

When X═CH, intermediates of Formula 2 can be prepared from intermediatesof Formula 3b by deprotection of G² followed by reductive amination. G²are amine protecting groups, such as Boc, Cbz and trifluoroacetamideetc.

Intermediates of Formula 3b can be prepared by N-alkylation of indole 4bwith commercially available alkyl halide 5b, where G³ is Br or I.Intermediates of Formula 4b can be prepared by removal of G⁴ fromintermediates of Formula 6b, where G⁴ is methanesulfonate orphenylsulfonate.

Intermediates of Formula 6b can be prepared by sequential Sonogashiracoupling reaction between aryl halides 7b (where G⁵ is Br or I) andpropargyl alcohols 8b, followed by cyclization, to give intermediates ofFormula 9b, followed by oxidation of the alcohol.

Intermediates of Formula 7b can be prepared from commercially availableaniline 10b via the following transformations: 1) Displacement offluorine with sodium alkyl sulfide R¹SNa (yielding 11b); 2) Halogenation(yielding 12b); 3) Protection of the aniline (yielding 13b); 4)Oxidation of the sulfide (yielding 7b).

In the second process, a compound of Formula I, where R¹=alkyl, R²═H andX═CH, can be prepared by oxidation of the thioether group inintermediates of Formula 1c. Intermediate 1c in turn can be preparedfrom coupling of reagents 1 and intermediates of Formula 2c via S_(N)Aror palladium catalyzed reactions.

Intermediates 2c can be prepared according to following scheme.

All patents, patent applications, books and literature cited in thespecification are hereby incorporated by reference in their entirety. Inthe case of any inconsistencies, the present disclosure, including anydefinitions therein will prevail.

The invention will be further described by reference to the followingdetailed examples, which are given for illustration of the invention,and are not intended to be limiting thereof.

Preparation 1 Tert-butyl1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate

Step 1

To a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoicacid (2.0 g, 9.20 mmol) in CH₂Cl₂ (40 mL) were added2-(benzylamino)ethanol (1.3 g, 8.80 mmol), HATU (5.30 g, 13.8 mmol) andEt₃N (2.80 g, 27.6 mmol) under N₂. The mixture was stirred at rtovernight. The mixture was diluted with water (20 mL) and extracted withEtOAc (3×30 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous Na₂SO₄, filtered, concentrated and purified bycolumn chromatography on silica gel to afford(R)-tert-butyl(1-(benzyl(2-hydroxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate(2.80 g, 88% yield) as a white solid. LC-MS m/z 351.2 [M+H]⁺.

Step 2

To a solution of(R)-tert-butyl(1-(benzyl(2-hydroxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate(2.80 g, 8.0 mmol) in CH₂Cl₂ (20 mL) were added Et₃N (1.60 g, 16 mmol)and MsCl (1.40 g, 12.0 mmol) dropwise at −10° C. under N₂. The mixturewas stirred at rt overnight. The mixture was quenched with water (20 mL)and extracted with CH₂Cl₂ (3×20 mL). The combined organic layers werewashed with brine (20 mL) and dried over anhydrous Na₂SO₄, filtered,concentrated to afford(R)-tert-butyl(1-(benzyl(2-chloroethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate(3.0 g, 100% yield) as a yellow solid, which was used for the next stepwithout further purification. LC-MS m/z 369.2 [M+H]⁺. ¹H NMR (CDCl₃ 400MHz): δ 7.37-7.28 (m, 3H), 7.22-7.20 (m, 2H), 5.27-5.18 (m, 1H),4.93-4.86 (m, 1H), 4.64-4.39 (m, 2H), 3.85-3.66 (m, 2H), 3.61-3.39 (m,2H), 2.03-1.97 (m, 1H), 1.45 (s, 9H), 0.98 (d, J=6.8 Hz, 3H), 0.93 (d,J=6.8 Hz, 3H).

Step 3

To a solution of(R)-tert-butyl(1-(benzyl(2-chloroethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate(2.0 g, 5.40 mmol) in DMF (30 mL) was added NaH (1.0 g, 27.0 mmol, 60%in oil mineral) at 0° C. under N₂. The mixture was stirred at rt for 2h. The mixture was quenched with water (20 mL) and extracted with EtOAc(3×20 mL). The combined organic layers were washed with brine (20 mL)and dried over anhydrous Na₂SO₄, filtered, concentrated and purified bycolumn chromatography to afford (R)-tert-butyl4-benzyl-2-isopropyl-3-oxopiperazine-1-carboxylate (1.13 g, 63% yield)as a white solid. LC-MS m/z 277.1 [M−56+H]⁺. ¹H NMR (CDCl₃ 400 MHz): δ7.38-7.29 (m, 3H), 7.29-7.22 (m, 2H), 5.02-4.86 (m, 1H), 4.49-4.39 (m,1H), 4.31-4.06 (m, 2H), 3.41-3.18 (m, 3H), 2.42-2.31 (m, 1H), 1.46 (s,9H), 1.12 (d, J=6.8 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H).

Step 4

To a three-necked bottle containing THF (10 mL) was bubbled with NH₃(gas) at −78° C. for 5 mins. Na (300 mg, 13.0 mmol) was added to themixture slowly at −78° C. After stirring for 30 min, (R)-tert-butyl4-benzyl-2-isopropyl-3-oxopiperazine-1-carboxylate (700 mg, 2.11 mmol)was added dropwise at −78° C. The mixture was stirred at −78° C. for 30min. The mixture was quenched with sat. aq NH₄Cl (10 mL) and extractedwith EtOAc (3×10 mL). The combined organic layers were washed with brine(10 mL), dried over anhydrous Na₂SO₄, filtered, concentrated andpurified by preparative TLC with PE/EtOAc 1/1 to afford tert-butyl2-isopropyl-3-oxopiperazine-1-carboxylate (300 mg, 59% yield) as a whitesolid. The product was found to be a racemic mixture. The cause ofracemization was not investigated. LC-MS m/z 187.1 [M−56+H]⁺, 265.1[M+Na]⁺. ¹H NMR (CDCl₃ 400 MHz): δ 6.29 (s, 1H), 4.55-3.99 (m, 2H),3.51-3.36 (m, 1H), 3.32-3.12 (m, 2H), 2.34-2.29 (m, 1H), 1.46 (s, 9H),1.09 (d, J=6.8 Hz, 3H), 0.99 (d, J=7.2 Hz, 3H).

Step 5

To a solution of tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate(200 mg, 0.83 mmol) in NMP (3 mL) was added2-bromo-4-(methylsulfonyl)aniline (207 mg, 0.83 mmol),(1R,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (12.0 mg, 0.08 mmol),K₃PO₄.3H₂O (660 mg, 2.48 mmol), Cul (16 mg, 0.08 mmol). The mixture wasstirred at 150° C. for 1 h under microwave. The mixture was diluted withwater (10 mL) and extracted with EtOAc (3×10 mL). The combined organiclayers were washed with brine (10 mL), dried over anhydrous Na₂SO₄,filtered, concentrated and purified by preparative TLC with CH₂Cl₂/MeOH35/1 to afford tert-butyl1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate(110 mg, 34% yield) as a white solid.

LC-MS m/z 394.1 [M+H]⁺. ¹H NMR (CDCl₃ 400 MHz): δ 7.94 (s, 1H),7.83-7.76 (m, 2H), 5.35-5.17 (m, 1H), 4.73-4.42 (m, 1H), 4.22-4.12 (m,1H), 4.11-3.99 (m, 1H), 3.53-3.37 (m, 1H), 3.03 (s, 3H), 2.38-2.27 (m,1H), 1.42 (s, 9H), 1.19 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H).

Preparation 2 (R)-2-tert-butyl 8-methyl1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2,8(1H)-dicarboxylate

Step 1

A solution of Cbz-D-Valine (500 g, 1.99 mol) and N-methylmorpholine(201.8 g, 1.99 mol) in anhydrous THF (8 L) was cooled to −15° C.,i-butylchlorofomate (299 g, 2.19 mol) was added dropwise under stirring.After 30 min, a solution of 1-amino-2,2-dimethyoxypropane (209.5 g, 1.99mol) in THF (1 L) was added slowly and the temperature was maintained at−15° C. for 2 h. The reaction mixture was washed with brine (2 L) andthe organic phase was concentrated to remove the THF. The residue wasdiluted with EtOAc (4 L), washed with 1N aqueous HCl (2×2 L), washedwith sat. NaHCO₃ (2 L) and Na₂CO₃ (2 L), and washed with brine (1.5 L).After drying over Na₂SO₄, the organic solvent was removed under reducepressure to afford(R)-benzyl(1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamateas a white solid (670 g, yield 99.5%), which was used for next stepwithout further purification. LC-MS m/z 360.9 [M+Na]⁺. ¹H NMR (CD₃OD 300MHz): δ 7.35-7.30 (m, 5H), 5.08 (s, 2H), 4.45-4.35 (m, 1H), 3.95-3.85(m, 1H), 3.34-3.25 (m, 8H), 2.10-1.90 (m, 1H), 0.94-0.91 (m, 6H).

Step 2

(R)-benzyl(1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate(335 g, 0.99 mol) was added in portions to a cooled TFA-H₂O (temperature<5° C., V_(TFA) V_(H2O)=7/3, 2 L), and the solution was stirred at rtfor 12 h. The solution was added slowly into a stirring cooled sat. aq.Na₂CO₃ (2.5 L) to keep the pH>8. Then the mixture was extracted withEtOAc (5×2 L). The combined organic layers were washed with brine (2 L),dried over anhydrous Na₂SO₄, filtered and evaporated in vacuo to give(R)-benzyl 2-isopropyl-3-oxo-3,4-dihydropyrazine-1(2H)-carboxylate as awhite solid (259 g, 95.4%), which was used for next step without furtherpurification. LC-MS m/z 274.9 [M+H]⁺. ¹H NMR (CD₃OD 300 MHz): δ7.36-7.34(m, 5H), 6.33-6.30 (m, 1H), 5.79-5.68 (m, 1H), 5.26-5.13 (m, 2H),4.38-4.29 (m, 1H), 2.01-1.96 (m, 1H), 1.00-0.84 (m, 6H).

Step 3

To a stirring solution of (R)-benzyl2-isopropyl-3-oxo-3,4-dihydropyrazine-1(2H)-carboxylate (400 g, 1.46mol) in DCE (2 L) was added Et₃SiH (424 g, 3.65 mol) and TFA (665 g, 5.8mol) at rt. The reaction was stirred under reflux for 36 h. After cooledto rt, the solution was concentrated to remove the solvent. The residuewas diluted with EtOAc (2 L), and it was added slowly into a stirringcooled sat. aq. NaHCO₃ (2 L) to make sure that the pH>8. The mixture wasextracted with EtOAc (2×2.5 L). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, filter and concentrated to give(R)-benzyl 2-isopropyl-3-oxopiperazine-1-carboxylate (402 g, yield99.75%), which was used for next step without further purification.LC-MS m/z 276.9 [M+H]⁺. ¹H NMR (DMSO-d₆ 400 MHz): δ 7.93 (s, 1H),7.39-7.31 (m, 5H), 5.09 (s, 2H), 4.06-4.01 (m, 1H), 3.99-3.92 (m, 1H),3.23-3.14 (m, 3H), 2.20-2.12 (m, 1H), 0.96-0.94 (m, 3H), 0.85 (d, J=6.0Hz, 3H).

Step 4

To a 1 L round-bottom flask containing (R)-benzyl2-isopropyl-3-oxopiperazine-1-carboxylate (50 g, 0.181 mol) in MeOH (800mL) was added Pd/C (dry, w/w 15%, 5 g). The mixture was stirred at rtunder H₂ (1 atm) overnight. When TLC and LCMS showed that the startingmaterial was consumed, (Boc)₂O (76.74 g, 0.352 mol) was added to thereaction mixture, and the mixture was stirred at rt overnight until theintermediate (R)-3-isopropylpiperazin-2-one was consumed. The mixturewas filtered and concentrated under vacuum to give a residue. Theresidue was purified by column chromatography on silica gel (elutingwith PE:EtOAc=3:1) to give (R)-tert-butyl2-isopropyl-3-oxopiperazine-1-carboxylate as a white solid (26 g, yield61%. For (R)-3-isopropyl-piperazin-2-one: LC-MS m/z 143.2 [M+H]⁺. ¹H NMR(HCl salt, CD₃OD 400 MHz): δ 3.95 (d, J=3.6 Hz, 1H), 3.65-3.39 (m, 4H),2.63-2.54 (m, 1H), 1.15 (d, J=6.8 Hz, 3H), 1.09 (d, J=7.2 Hz, 3H). For(R)-tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate: LC-MS m/z186.9 [M−56+H]⁺. ¹H NMR (DMSO-d₆ 400 MHz): δ 7.93 (s, 1H), 4.02-3.82 (m,2H), 3.17-3.15 (m, 3H), 2.16 (s, 1H), 1.41 (s, 9H), 0.98 (d, J=6.8 Hz,3H), 0.89 (d, J=6.4 Hz, 3H).

Step 5

Under N₂ atmosphere, NaH (8.8 g, 0.22 mol, 60% in mineral oil, 1.1 eq.)was added in portions at −10° C. to a 1 L three-neck flask containing(R)-tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (26.7 g, 0.11mol) in DMF (300 mL). The mixture was stirred at −10° C. for 30 min. Themixture was added dropwise to a 1 L three-neck flask containing methyl2,4-difluoro-5-nitrobenzoate (26.3 g, 0.121 mol, 1.1 eq.) in DMF (200mL) at −20° C. over 10 min. After addition, the resulting mixture wasstirred between −20° C. and −30° C. for another 10 min. The reaction wasquenched with sat. aq. ammonium chloride (200 mL) and then water (800mL). The aqueous layer was extracted with EtOAc (3×1 L). The combinedorganic layers were washed with water (3×1 L) and brine, and then driedover anhydrous Na₂SO₄. After the mixture was filtered and the filter wasevaporated under vacuum, the residue was purified by columnchromatography on silica gel eluting with PE:EtOAc 8:1-4:1 to give(R)-tert-butyl4-(5-fluoro-4-(methoxycarbonyl)-2-nitrophenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate(32 g, 66.3% yield) as a yellow solid. LC-MS MS (ESI) m/z 384.1[M−56+H]⁺, 462.1 [M+Na]⁺. ¹H NMR (CDCl₃ 300 MHz): δ 8.63 (d, J=6.9 Hz,1H), 7.16 (d, J=10.2 Hz, 1H), 4.61-4.30 (m, 2H), 3.97-3.89 (m, 4H),3.62-3.48 (m, 2H), 2.40-2.34 (m, 1H), 1.49 (s, 9H), 1.08 (d, J=6.9 Hz,3H), 1.01 (d, J=6.9 Hz, 3H).

Step 6

To a 1 L round-bottom flask containing (R)-tert-butyl4-(5-fluoro-4-(methoxycarbonyl)-2-added NaSMe (14.3 g, 0.204 mmol, 3eq.). The mixture was stirred at rt for 1 h. Water (500 mL) was addedand the mixture was concentrated under vacuum to remove THF. The aqueouslayer was extracted with EtOAc (3×800 mL). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum to give (R)-tert-butyl2-isopropyl-4-(4-(methoxycarbonyl)-5-(methylthio)-2-nitrophenyl)-3-oxopiperazine-1-carboxylate(31.9 g, 100% yield) as a yellow solid. The residue was used directlyfor the next step without further purification. LC-MS MS (ESI) m/z 412.1[M−56+H]⁺, 490.2 [M+Na]⁺.

Step 7

To a 2 L round-bottom flask containing (R)-tert-butyl2-isopropyl-4-(4-(methoxycarbonyl)-5-(methylthio)-2-nitrophenyl)-3-oxopiperazine-1-carboxylate(crude 91.7 g, 0.196 mol) in CH₂Cl₂ (1 L) was added m-CPBA (84.6 g, 0.49mmol, 2.5 eq). The mixture was stirred at rt overnight. Sat. Na₂S₂O₃ wasadded slowly to quench the reaction. The mixture was extracted withCH₂Cl₂ (4×3 L). The combined organic layers were washed successivelywith Na₂S₂O₃ solution (500 mL), NaHCO₃ solution (500 mL) and brine,dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by column chromatography on silica gel eluting withdichloromethane to give (R)-tert-butyl2-isopropyl-4-(4-(methoxycarbonyl)-5-(methylsulfonyl)-2-nitrophenyl)-3-oxopiperazine-1-carboxylate(83.7 g, 85.4% yield) as a yellow solid. LC-MS MS (ESI) m/z 444.0[M−56+H]⁺, 522.1 [M+Na]⁺. ¹H NMR (CDCl₃ 300 MHz): δ 8.29 (s, 1H), 8.12(s, 1H), 4.61-4.17 (m, 2H), 4.00-3.94 (m, 4H), 3.70-3.60 (m, 1H),3.51-3.43 (m, 4H), 2.39-2.32 (m, 1H), 1.50 (s, 9H), 1.07 (d, J=6.9 Hz,3H), 1.01 (d, J=6.9 Hz, 3H).

Step 8

To a 1 L round-bottom flask containing (R)-tert-butyl2-isopropyl-4-(4-(methoxycarbonyl)-5-(methylsulfonyl)-2-nitrophenyl)-3-oxopiperazine-1-carboxylate(26.3 g, 0.0526 mol) in THF (200 mL) and methanol (200 mL) was addedRaney Nickel (in H₂O, 4 g). The mixture was stirred under H₂ (30 psi) atrt overnight. The mixture was filtered and concentrated under vacuum togive (R)-tert-butyl4-(2-amino-4-(methoxycarbonyl)-5-(methylsulfonyl)phenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate(24.7 g, 100% yield) as a yellow solid. The residue was used directlyfor the next step without further purification. LC-MS MS (ESI) m/z 414.0[M−56+H]⁺, 492.0 [M+Na]⁺. ¹H NMR (CDCl₃ 300 MHz): δ 7.77 (brs, 1H), 7.04(s, 1H), 4.68-4.45 (m, 1H), 4.45-4.38 (m, 2H), 3.92 (s, 3H), 3.70-3.58(m, 1H), 3.58-3.41 (m, 1H), 3.30 (s, 3H), 2.49-2.25 (m, 1H), 1.50 (s,9H), 1.12 (d, J=6.9 Hz, 3H), 1.05 (d, J=6.9 Hz, 3H).

Step 9

To a 1 L round-bottom flask containing (R)-tert-butyl4-(2-amino-4-(methoxycarbonyl)-5-(methylsulfonyl)phenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate(25 g, 0.0532 mol) in dichloromethane (500 mL) was added Et₃N (64.5 g,0.638 mol, 12 eq.) and SiCl₄ (27.1 g, 0.160 mol, 3 eq.). The mixture wasstirred at rt overnight. The mixture was added dropwise to aq. NaHCO₃solution (54.1 g in 1 L of water, 0.644 mol, 12.1 eq.) at 0° C. slowlyand adjusted to pH=8. The mixture was filtered and the aqueous layer wasextracted with dichloromethane (3×600 mL). The combined organic layerswere washed with brine, and then dried over anhydrous Na₂SO₄. Themixture was filtered and concentrated under vacuum to give the residue.The residue was purified by column chromatography on silica gel elutingwith PE:EtOAc 2:1 to give (R)-2-tert-butyl 8-methyl1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2,8(1H)-dicarboxylate(13.2 g, 55% yield) as a pale yellow solid. Analytical chiral HPLC:t_(R)=9.03 min in 15 min chromatography (Method: OD-3_3_5_40_2.5 ML).LC-MS MS (ESI) m/z 452.2 [M+H]⁺. ¹H NMR (CD₃OD 400 MHz): δ 8.31 (s, 1H),8.01 (s, 1H), 5.30-5.18 (m, 1H), 4.70-4.52 (m, 1H), 4.47 (dd, J=3.2 and12.4 Hz, 1H), 4.18 (dt, J=5.2 and 11.6 Hz, 1H), 3.98 (s, 3H), 3.70-3.52(m, 1H), 3.44 (s, 3H), 2.50-2.38 (m, 1H), 1.53 (s, 9H), 1.25 (d, J=6.8Hz, 3H), 1.06 (d, J=6.8 Hz, 3H).

Preparation 31-isopropyl-7-(methylthio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole

Step 1

To a solution of 6-bromo-1H-indole (5 g, 25.50 mmol) in anhydrous THF(60 mL) at 0° C. was added KH (6.80 g, 51.00 mmol, 30% wt in mineraloil). After stirring for 30 min and cooling to −78° C., t-BuLi (39.23mL, 51.0 mmol, 1.3 M) was added to the formed mixture under nitrogen.After 30 min, 1,2-dimethyldisulfane (4.80 g, 51.0 mmol) was added to theformed mixture. The reaction mixture was stirred at −78° C. for 1 h. Themixture was quenched with sat. NH₄Cl (30 mL) at −78° C. slowly (Caution:flame), adjusted pH=7 with 1 N aqueous phosphoric acid and extractedwith EtOAc (50 mL×3). The combined organic layers were dried overanhydrous sodium sulfate, filtered, concentrated and purified by columnchromatography on silica gel eluted with PE/EtOAc 10:1 to give6-(methylthio)-1H-indole (3.9 g, 93.67% yield) as a grey solid. LC-MS MS(ESI) m/z 164.1 [M+H]⁺. ¹H NMR (CDCl₃ 400 MHz): δ 8.14 (brs, 1H), 7.56(d, J=8.0 Hz, 1H), 7.37 (s, 1H), 7.18-7.11 (m, 1H), 6.56-6.51 (m, 1H),2.52 (s, 3H).

Step 2

To a solution of 6-(methylthio)-1H-indole (1 g, 6.13 mmol), NaOH (4.90g, 122.6 mmol) and Bu₄NHSO₄ (207.8 mg, 0.613 mmol) in dichloromethane(20 mL) was added benzenesulfonyl chloride (1.29 g, 7.36 mmol). Thereaction mixture was stirred at rt overnight. The mixture was quenchedwith water (30 mL) and extracted with dichloromethane (30 mL×3). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered, concentrated and purified by column chromatography on silicagel eluted with PE/EtOAc 10:1 to afford6-(methylthio)-1-(phenylsulfonyl)-1H-indole (1.1 g, 59.18% yield) as awhite solid. LC-MS MS (ESI) m/z 304.0 [M+H]⁺. ¹H NMR (CDCl₃ 400 MHz): δ7.93-7.75 (m, 3H), 7.58-7.41 (m, 5H), 7.17 (dd, J₁=8.0 Hz, J₂=1.6 Hz,1H), 6.63-6.60 (m, 1H), 2.53 (s, 3H).

Step 3

To a solution of 6-(methylthio)-1-(phenylsulfonyl)-1H-indole (890 mg,2.93 mmol) in anhydrous THF (10 mL) at 0° C. under nitrogen was addedn-BuLi (5.86 mL, 14.65 mmol, 2.5 M). After stirring for 30 min,isobutyraldehyde (1.05 g, 14.65 mmol) was added to the formed mixture.The reaction mixture was stirred at 0° C. for 1 h. The mixture wasquenched with sat. NH₄Cl (10 mL) at 0° C. and extracted with EtOAc (20mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered, concentrated and purified by column chromatography onsilica gel eluted with PE/EtOAc 20:1 to give2-methyl-1-(6-(methylthio)-1H-indol-2-yl)propan-1-one (440 mg, 64.28%yield) as a colorless oil. LC-MS MS (ESI) m/z 234.1 [M+H]+. ¹H NMR(CDCl₃ 400 MHz): δ 8.86 (brs, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.19 (s, 1H),7.14-7.11 (m, 1H), 7.01 (dd, J₁=8.4 Hz, J₂=1.6, 1H), 3.42-3.38 (m, 1H),2.47 (s, 3H), 1.20 (d, J=6.8 Hz, 6H).

Step 4

To a solution of 2-methyl-1-(6-(methylthio)-1H-indol-2-yl)propan-1-one(600 mg, 2.57 mmol) and Bu₄NBr (4.12 g, 12.85 mmol) in 9 N NaOH (10 mL,cooled) was added tert-butyl(2-bromoethyl)carbamate (2.87 g, 12.85mmol). The reaction mixture was stirred at rt for 72 h. The mixture wasdiluted with water (20 mL) at 0° C., extracted with EtOAc (20 mL×3). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered, concentrated and purified by column chromatography on silicagel eluting with PE/EtOAc 10:1 to affordtert-butyl(2-(2-isobutyryl-6-(methylthio)-1H-indol-1-yl)ethyl)carbamate(200 mg, 20.66% yield) as a colorless oil. LC-MS MS (ESI) m/z 321.1[M−56+H]⁺, 277.1 [M−100+H]⁺. ¹H NMR (CDCl₃ 400 MHz): δ 7.57 (d, J=8.4Hz, 1H), 7.38 (s, 1H), 7.29 (s, 1H), 7.10 (d, J=8.4 Hz, 1H), 4.80 (brs,1H), 4.62 (t, J=6.4 Hz, 2H), 3.58-3.42 (m, 3H), 2.58 (s, 3H), 1.38 (s,9H), 1.24 (d, J=6.8 Hz, 6H).

Step 5

To a solution affordtert-butyl(2-(2-isobutyryl-6-(methylthio)-1H-indol-1-yl)ethyl)carbamate(200 mg, 0.53 mmol) in dichloromethane (9 mL) at 0° C. was added TFA (1mL). The reaction mixture was stirred at rt for 1 h. The mixture wasconcentrated (T<25° C.), treated with water (5 mL), adjusted pH=11 withsat. NaHCO₃ and extracted with EtOAc (20 mL×3). The combined organiclayers were dried over anhydrous sodium sulfate, filtered, concentratedto afford1-(1-(2-aminoethyl)-6-(methylthio)-1H-indol-2-yl)-2-methylpropan-1-one(210 mg, 100% yield) as a colorless oil. LC-MS MS (ESI) m/z 258.8[M−18+H]+.

Step 6

To a solution of1-(1-(2-aminoethyl)-6-(methylthio)-1H-indol-2-yl)-2-methylpropan-1-one(200 mg, 0.724 mmol) in MeOH (5 mL) was added Et₃N (219.3 mg, 2.172mmol). The reaction mixture was stirred at 60° C. for 1 h. Then NaBH₄(82.53 mg, 2.172 mmol) was added to the formed mixture. The mixture wasstirred at 60° C. for another 1 h. The mixture was concentrated, treatedwith water (10 mL) and extracted with EtOAc (20 mL×3). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered,concentrated and purified by preparative TLC on silica gel eluted withPE/EtOAc 1:1 to afford1-isopropyl-7-(methylthio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (80mg, 42.46% yield, store at 0° C.) as a colorless oil. LC-MS of1-Isopropyl-7-methylsulfanyl-3,4-dihydro-pyrazino[1,2-a]indole MS (ESI)m/z 259.1 [M+H]⁺. LC-MS of1-isopropyl-7-(methylthio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole MS(ESI) m/z 261.2 [M+H]⁺. 1H NMR (CDCl₃ 400 MHz): δ 7.41 (d, J=8.4 Hz,1H), 7.20 (s, 1H), 7.05 (dd, J₁=8.4 Hz, J₂=1.6 Hz, 1H), 6.12 (s, 1H),4.02-3.97 (m, 2H), 3.86-3.80 (m, 1H), 3.46-3.42 (m, 1H), 3.16-3.10 (m,1H), 2.48 (s, 3H), 2.32-2.27 (m, 1H), 1.09 (d, J=6.8 Hz, 3H), 0.86 (d,J=6.8 Hz, 3H).

Preparation 48-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole

Step 1

To a solution of ethyl 4-amino-2-fluorobenzoate (12 g, 65.5 mmol) in DMF(100 mL) was added NaSMe (9.17 g, 131 mmol) and the mixture was stirredat 60° C. for 20 h. After cooling to rt, the reaction was diluted withH₂O and extracted with EtOAc (3×100 mL). The combined organic phaseswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to afford ethyl4-amino-2-(methylthio)benzoate.

To a pre-heated 60° C. solution of ethyl 4-amino-2-(methylthio)benzoate(65 mmol) in acetic acid (150 mL) was added ICl/AcOH solution (1M, 72mL, 72 mmol) dropwise during 40 min and the temperature was maintainedat 60° C. for 3 h. After cooling to rt the reaction was diluted withEtOAc (500 mL) and washed with 5% sodium thiosulfate solution (3×100 mL)and brine (200 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude product was purified by silica gelchromatography (0-20% EtOAc/Hexanes) to afford ethyl4-amino-5-iodo-2-(methylthio)benzoate (13.67 g, 53% yield). For ethyl4-amino-2-(methylthio)benzoate: LC-MS m/z 212 [M+H]⁺. For ethyl4-amino-5-iodo-2-(methylthio)benzoate: LC-MS m/z 338 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): δ 8.29 (s, 1H), 6.47 (s, 1H), 4.49 (br s, 2H), 4.31 (q,J=7.2 Hz, 2H), 2.38 (s, 3H), 1.37 (t, J=7.2 Hz, 3H).

Step 2

To a solution of ethyl 4-amino-5-iodo-2-(methylthio)benzoate (13.6 g, 40mmol) in DCM (100 mL) was added Et₃N (13.8 mL, 100 mmol), followed byMsCl (7.7 mL, 100 mmol) at 0° C. After addition the mixture was stirredat rt for 2 h. 1N HCl solution (50 mL) was added to the mixture and theaqueous phase was extracted with DCM (1×100 mL). The organic solutionwas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give ethyl5-iodo-4-(N-(methylsulfonyl)methylsulfonamido)-2-(methylthio)benzoate.The crude reaction mixture above was dissolved into 100 mL THF. To thissolution was added TBAF THF solution (1 M, 100 mL) and the mixture wasstirred at rt for 2 h. H₂O was added to the mixture and the aqueousphase was extracted with EtOAc (3×100 mL). The combined organic solutionwas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to afford ethyl5-iodo-4-(methylsulfonamido)-2-(methylthio)benzoate. It was used fornext step without further purification. For ethyl5-iodo-4-(N-(methylsulfonyl)methylsulfonamido)-2-(methylthio)benzoate:LC-MS m/z 494 [M+H]⁺. For ethyl5-iodo-4-(methylsulfonamido)-2-(methylthio)benzoate: LC-MS m/z 415[M+H]⁺.

Step 3

To a solution of ethyl5-iodo-4-(methylsulfonamido)-2-(methylthio)benzoate (crude, from step 2)in dry toluene (200 mL) at 0° C. was added diisobutylaluminium hydride(1.0 M in toluene, 100 mL, 100 mmol) slowly. After addition, the mixturewas stirred at 0° C. for 3 h and quenched with methanol/H₂O (1/1). Thereaction mixture was poured into a vigorously stirred solution ofpotassium sodium tartrate (1M, 300 mL) and stirred vigorously for 2 h,after which time it settled to two clear phases. The organic layer wasseparated, and the aqueous layer was extracted with EtOAc (3×200 mL).The combined organic solution was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudeproduct was purified by silica gel chromatography (0-40% EtOAc/Hexanes)to affordN-(4-(hydroxymethyl)-2-iodo-5-(methylthio)phenyl)methanesulfonamide(11.9 g, 80% yield for two steps). LC-MS m/z 356 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): δ 7.82 (s, 1H), 7.49 (s, 1H), 4.67 (s, 2H), 2.99 (s, 3H),2.50 (s, 3H).

Step 4

To a stirred solution ofN-(4-(hydroxymethyl)-2-iodo-5-(methylthio)phenyl)methanesulfonamide (6.4g, 17.2 mmol) and imidazole (1.76 g, 25.8 mmol) in CH₂Cl₂ (100 mL) andDMF (50 mL) at 0° C. was added tert-butyldiphenylsilyl chloride (5.8 mL,22.4 mmol). The mixture was allowed to stir at rt overnight. The mixturewas diluted with CH₂Cl₂ (100 mL), washed with 1N HCl solution, sat. aq.NaHCO₃ and brine, dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo to affordN-(4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-iodo-5-(methylthio)phenyl)methanesulfonamide.It was used for next step without further purification.

A suspension of crudeN-(4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-iodo-5-(methylthio)phenyl)methanesulfonamide,mCPBA (8.9 g, 51.6 mmol) in CH₂Cl₂ (100 mL) was stirred for 2 h at rt.Sat. aq. NaHCO₃ (50 mL) and Na₂S₂O₃ (50 mL) were added and the layersseparated. The aqueous layer was extracted with CH₂Cl₂ (2×100 mL).Combined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography over silica gel eluting with EtOAc/hexanes (3/7) toprovideN-(4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-iodo-5-(methylsulfonyl)phenyl)methanesulfonamide(8.8 g, 80% yield for two steps). ForN-(4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-iodo-5-(methylthio)phenyl)methanesulfonamide:LC-MS m/z 612 [M+H]⁺. ForN-(4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-iodo-5-(methylsulfonyl)phenyl)methanesulfonamide:LC-MS m/z 644 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.25 (s, 1H), 8.08 (s,1H), 7.67-7.65 (m, 4H), 7.46-7.37 (m, 6H), 6.77 (s, 1H), 5.05 (s, 2H),3.11 (s, 3H), 2.83 (s, 3H), 1.12 (s, 9H).

Step 5

PdCl₂(PPh₃)₂ (277 mg, 0.38 mmol) and CuI (73 mg, 0.38 mmol) were addedto a solution ofN-(4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-iodo-5-(methylsulfonyl)phenyl)methanesulfonamide(2.45 g, 3.8 mmol) in THF (20 mL) and Et₃N (10 mL). The mixture waspurged with nitrogen for 10 mins followed by addition of4-methylpent-1-yn-3-ol (745 mg, 7.6 mmol) and stirred at 65° C. for 8 h.The reaction mixture was diluted with EtOAc (50 mL) and washed with 1NHCl (50 mL). The organic layer was separated, and the aqueous layer wasextracted with EtOAc (3×50 mL). The combined organic solution was washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography oversilica gel eluting with EtOAc/hexanes (3/7) to provide1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,6-bis(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-ol(2.1 g, 90% yield). LC-MS m/z 614 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ8.68 (s, 1H), 7.90 (s, 1H), 7.71-7.67 (s, 4H), 7.46-7.35 (m, 6H), 6.77(s, 1H), 5.21 (d, J=3.2 Hz, 2H), 6.94 (t, J=6.8 Hz, 1H), 3.22 (s, 3H),2.90 (s, 3H), 2.61 (d, J=6.8 Hz, 1H), 2.37-2.32 (m, 1H), 1.12 (s, 9H),1.05 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H). ¹³C NMR (100 MHz,CDCl₃): δ 147.25, 135.54, 135.28, 135.00, 133.66, 133.00, 132.89,129.96, 127.85, 121.68, 115.96, 108.69, 72.30, 62.98, 44.33, 41.59,32.88, 26.89, 20.23, 19.30, 17.61.

Step 6

To a stirred solution of1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,6-bis(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-ol(2.3 g, 3.8 mmol) in dry CH₂Cl₂ (25 mL) was added Dess-Martin periodiane(1.94 g, 4.56 mmol) in one portion. The mixture was allowed to stir atrt for 2 h. The reaction was quenched with a solution of Na₂S₂O₃ (5 g in30 mL H₂O) and sat. NaHCO₃ solution (40 mL). The mixture was extractedwith EtOAc (3×80 mL). The combined organic solution was washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography oversilica gel eluting with EtOAc/hexanes (2/8) to provide1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,6-bis(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-one(2.0 g, 86% yield). LC-MS m/z 612 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ8.69 (s, 1H), 8.03 (s, 1H), 7.70-7.68 (m, 4H), 7.46-7.36 (m, 6H), 7.22(s, 1H), 5.20 (s, 2H), 3.80 (s, 3H), 3.36 (m, 1H), 2.89 (s, 3H), 1.29(d, J=6.8 Hz, 6H), 1.13 (s, 9H). ¹³C NMR (100 MHz, CDCl₃): δ 197.83,141.53, 136.69, 136.05, 135.50, 135.04, 132.81, 131.14, 129.99, 127.88,123.17, 117.12, 114.21, 62.87, 44.19, 44.03, 39.09, 26.88, 19.30, 18.41.

Step 7

To a stirred solution of1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,6-bis(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-one(780 mg, 1.27 mmol) in THF/methanol (15 mL/15 mL) was added Cs₂CO₃ (1.25g, 3.83 mmol) in one portion. The mixture was allowed to stir at rt for4 h and concentrated in vacuo to afford the crude product1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-6-(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-one.It was used for the next step reaction without further purification.

To a solution of crude1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-6-(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-one,2-(Boc-amino)ethyl bromide (2.8 g, 12 mmol) and tetrabutylammoniumiodide (235 mg, 0.63 mmol) in CH₂Cl₂/toluene (2 mL/4 mL) was added 40%NaOH aq. solution (20 mL). The mixture was allowed to stir at rt for 20h. The reaction mixture was diluted with CH₂Cl₂ (40 mL) and washed withH₂O (50 mL). The organic layer was separated, and the aqueous layer wasextracted with CH₂Cl₂ (4×50 mL). The combined organic solution waswashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography over silica gel eluting with CH₂Cl₂/methanol (95/5) toprovidetert-butyl(2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-isobutyryl-6-(methylsulfonyl)-1H-indol-1-yl)ethyl)carbamate(300 mg, 35% yield for two steps). For1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-6-(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-one:LC-MS m/z 556 [M+Na]⁺. Fortert-butyl(2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-isobutyryl-6-(methylsulfonyl)-1H-indol-1-yl)ethyl)carbamate:LC-MS m/z 699 [M+Na]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.20 (s, 1H), 7.93 (s,1H), 7.72 (dd, J₁=8.0 Hz, J₂=1.6 Hz, 4H), 7.47-7.35 (m, 7H), 5.21 (s,2H), 4.72 (d, J=6.8 Hz, 2H), 3.55 (d, J=6.8 Hz, 2H), 3.33-3.26 (m, 1H),3.00 (s, 3H), 1.46 (s, 9H), 1.30 (d, J=6.4 Hz, 3H), 1.28 (d, J=6.4 Hz,3H), 1.11 (s, 9H).

Step 8

To a solution oftert-butyl(2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-isobutyryl-6-(methylsulfonyl)-1H-indol-1-yl)ethyl)carbamate(250 mg, 0.37 mmol) in CH₂Cl₂ (5.0 mL) was added trifluoroacetic acid(1.0 mL) and the mixture was allowed to stir at rt for 1 h. The excessamount of TFA was removed by azeotropic evaporation with toluene underreduced pressure. The residue was redissolved in CH₂Cl₂ (5 mL) and Et₃N(0.5 mL) was added. The reaction mixture was stirred at rt for 45 minand concentrated in vacuo. The residue was purified by flashchromatography over silica gel eluting with CH₂Cl₂/methanol (98/2) toprovide8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indole(135 mg, 65% yield). LC-MS m/z 559 [M+H]⁺.

Step 9

A solution of8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indole(140 mg, 0.25 mmol), 10% Palladium on charcoal (37 mg, 0.025 mmol) andmethanol (5 mL) was stirred at rt under 1 atmosphere of hydrogen for 3h. The mixture was filtered through Celite® and the Celite® was washedthoroughly with methanol. Combined solvent was removed under reducedpressure to afford8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole.It was used directly without further purification. A small portion ofproduct was purified by chromatography for characterization. LC-MS m/z561 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.00 (s, 1H), 7.73-7.70 (m, 5H),7.47-7.40 (m, 6H), 6.36 (s, 1H), 5.20 (d, J=2.0 Hz, 2H), 4.24-4.19 (m,1H), 4.11-4.00 (m, 2H), 3.52-3.47 (m, 1H), 3.20-3.13 (m, 1H), 3.03 (s,3H), 2.47-2.39 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.09 (s, 9H), 0.96 (d,J=6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 143.06, 135.68, 134.04,133.31, 131.52, 130.26, 129.79, 129.51, 127.77, 121.39, 111.22, 97.14,63.76, 59.28, 45.00, 42.94, 42.47, 31.55, 26.94, 19.72, 19.31, 16.49.

Preparation 5 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanoneMethod 1

At −78° C., to a solution of2-chloro-4-(trifluoromethyl)pyrimidine-5-carbonyl chloride (2.45 g, 10mmol) in dry THF (50 mL) was added MeMgCl THF solution (3.0 M, 4 mL, 12mmol) slowly and the reaction mixture was allowed to stir at −78° C. for45 min. Sat. aq. NH₄Cl (2 mL) and water (4 mL) were added. The aqueouslayer was extracted with EtOAc (2×10 mL), and the combined extracts weredried with Na₂SO₄ and concentrated under reduced pressure. The cruderesidue was purified by silica chromatography eluting with EtOAc/hexanes(1/9) to give to give1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (675 mg, 30%yield). LC-MS m/z 225 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.86 (s, 1H),2.65 (s, 3H).

Method 2

To a solution of 1,1,1-trifluoropentane-2,4-dione (200 g, 1.30 mol) inethanol (200 mL) were added urea (78 g, 1.30 mol) and CH(OEt)₃ (211.5 g,1.43 mol). The mixture was stirred at 80° C. for 4 h. The resultingslurry was filtered. The filter cake was suspended in methanol (300 mL)and MeONa (77.2 g, 1.43 mol) was added. The mixture was stirred atreflux for 5 h, followed by slow addition of HCl (4N) to pH 3 at rt. Theresulting slurry was filtered and the filter cake was dried under vacuumto give compound (E)-1-(2-acetyl-4,4,4-trifluoro-3-oxobut-1-en-1-yl)urea(196 g, 67.3% yield) as a white solid. ¹H NMR (DMSO-d₆ 300 MHz): (Z/E) δ10.15-10.13 (m, 1H), 8.64 (s, 1H), 7.69-7.66 (m, 2H), 2.25 (s, 3H).LC-MS MS (ESI) m/z 206.8 [M−18+H]⁺.

A mixture of compound(E)-1-(2-acetyl-4,4,4-trifluoro-3-oxobut-1-en-1-yl)urea (55 g, 0.25 mol)and POCl₃ (240.7 g, 1.57 mol) was stirred at 100° C. for 3 h. Themixture was added dropwise to water (1.5 L) at rt and extracted withEtOAc (3×500 mL). The combined organic layers were washed with brine(500 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography eluting with PE/EtOAc 3/1to give compound 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone(23.5 g, 42.7% yield) as a pale-yellow oil. ¹H NMR (CDCl₃ 300 MHz): δ8.80 (s, 1H), 2.58 (s, 3H). ¹⁹F NMR (920-083-1A CDCl₃ 400 MHz): δ −65.5ppm. ¹³C NMR (903-158-1A CDCl₃ 400 MHz): δ 195.9, 162.3, 160.1, 153.8(dd, J=50 Hz), 130.9, 119.5 (dd, J=366 Hz), 30.7.

1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)propan-1-one and1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)butan-1-one

The title compounds were prepared by method 1 using appropriate Grignardreagents.

Preparation 6 5-bromo-2-chloro-4-(trifluoromethyl)pyrimidine

The title compound was prepared using a modified procedure based onOndi, L. et al., Eur. J. Org. Chem. 2004, 3714.

A mixture of 4-(trifluoromethyl)pyrimidin-2-ol (6.05 g, 36.9 mmol), KOAc(10.85 g, 3 eq.), acetic acid (80 mL), and bromine (5.9 g, 1eq.) washeated for 2 h at 80° C. After being cooled to rt, the mixture wasconcentrated. The residue was partitioned between EtOAc and water. Theaqueous layer was extracted with EtOAc (2×). The combined organic layerswere washed with brine, dried over Na₂SO₄. After filtration andconcentration, the crude white solid product (9.38 g, quant. yield) wasused for next steps without further purification.

A mixture of 5-bromo-4-(trifluoromethyl)pyrimidin-2-ol (1.35 g, 5.56mmol), POCl₃ (15 mL), and DMF (2 drops, cat. Amount) was heated for 2 hat 80° C. The mixture was cooled to 0° C. by ice/water bath. Some icepellets were added to the stirred mixture (exotherm). After stirring for20 min. (the ice added should have melted), some sat. aq. NaHCO₃ (c.a.15 mL) was added carefully to neutralize some acid. The mixture wasextracted with hexanes (3×). The combined organic layers were washedwith brine, dried over Na₂SO₄. After filtration and concentration (byrotavapor only! The product is volatile),5-bromo-2-chloro-4-(trifluoromethyl)pyrimidine, as a clear oil (1.32 g,91% yield) was used as crude for next steps without furtherpurification.

Example 11-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone

To a solution of tert-butyl1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate(30 mg, 0.08 mmol, from preparation 1) in CH₂Cl₂ (1 mL) was added TFA(0.2 mL) under N₂. The mixture was stirred at rt for 1 h. The mixturewas concentrated to afford1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine(30 mg, TFA salt) as a yellow solid, which was used for the next stepwithout further purification.

To a solution of1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine(7.50 mg, 0.03 mmol) in DMSO (1 mL) were added1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (11.5 mg, 0.05mmol) and DIEA (9.90 mg, 0.08 mmol) under N₂. The mixture was stirred at100° C. for 2 h. The mixture was diluted with water (10 mL) andextracted with EtOAc (3×10 mL). The combined organic layers were washedwith brine (10 mL), dried over anhydrous Na₂SO₄, filtered, concentratedand then purified by preparative HPLC to afford a racemic mixture of1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone(2.40 mg, 20% yield) as a white solid. LC-MS m/z 482.1 [M+H]⁺. ¹H NMR(CD₃OD 400 MHz): δ 8.76 (s, 1H), 8.02 (s, 1H), 7.91 (d, J=8.4 Hz, 1H),7.84-7.83 (m, 1H), 6.15 (d, J=8.0 Hz, 1H), 5.45 (d, J=13.6 Hz, 1H),4.42-4.36 (m, 1H), 4.20 (brs, 1H), 3.91-3.80 (m, 1H), 3.09 (s, 3H),2.60-2.46 (m, 4H), 1.34 (d, J=6.8 Hz, 3H), 1.09 (d, J=6.0 Hz, 3H).

Example 22-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol

To a solution of1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone(20 mg, 0.04 mmol, prepared according to example 1) in THF (5 mL) wasadded MeMgBr (0.6 mL, 0.20 mmol) dropwise at 0° C. under N₂. The mixturewas stirred at 0° C. for 2 h. The mixture was quenched with sat. aq.NH₄Cl (10 mL) and extracted with CH₂Cl₂ (3×10 mL). The combined organiclayers were washed with brine (10 mL), dried over anhydrous Na₂SO₄,filtered, concentrated and then purified by preparative TLC to afford aracemic mixture of2-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol(6.90 mg, 33% yield) as a white solid. LC-MS m/z 498.2 [M+H]⁺. ¹H NMR(CDCl₃ 400 MHz): δ 8.79 (s, 1H), 7.99 (d, J=1.2 Hz, 1H), 7.90-7.81 (m,2H), 6.08 (d, J=8.0 Hz, 1H), 5.35 (dd, J=4.4 and 14.0 Hz, 1H), 4.33-4.27(m, 1H), 4.25-4.12 (m, 1H), 3.88-3.73 (m, 1H), 3.09 (s, 3H), 2.57-2.48(m, 1H), 1.99 (s, 1H), 1.66 (s, 6H), 1.32 (d, J=6.8 Hz, 3H), 1.09 (d,J=6.8 Hz, 3H).

Example 3 Ethyl2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate

To a solution of1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine(5.0 mg, 0.02 mmol, prepared according to example 1) in DMSO (1 mL) wasadded ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (8.7mg, 0.03 mmol), DIEA (6.6 mg, 0.05 mmol) under N₂. The mixture wasstirred at 100° C. for 2 h. The mixture was diluted with water (5 mL)and extracted with EtOAc (3×5 mL). The combined organic layers werewashed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered,concentrated and then purified by preparative TLC to afford a racemicmixture of ethyl2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate(5.6 mg, 64% yield) as a white solid. LC-m/z 512.2 [M+H]⁺. ¹H NMR (CDCl₃400 MHz): δ 8.98 (s, 1H), 8.07-7.98 (m, 1H), 7.93-7.83 (m, 2H), 6.16 (d,J=6.4 Hz, 1H), 5.53-5.41 (m, 1H), 4.43-4.32 (m, 3H), 4.28-4.16 (m, 1H),3.92-3.79 (m, 1H), 3.09 (s, 3H), 2.61-2.46 (m, 1H), 1.40 (s, 3H),1.38-1.32 (m, 3H), 1.08 (d, J=6.8 Hz, 3H).

Example 4(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanol

To a solution of ethyl2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate(10 mg, 0.02 mmol, prepared according to example 3) in anhydrous toluene(0.5 mL) was added DIBAL-H (0.2 mL, 0.20 mmol, 1M in THF) dropwise at−78° C. under N₂. The mixture was stirred at −78° C. for 2 h. Sat. NH₄Cl(5 mL) at −78° C. was added to the mixture, which was then extractedwith EtOAc (3×5 mL). The combined organic layers were washed with brine(5 mL), dried over anhydrous Na₂SO₄, filtered, concentrated and thenpurified by basic preparative HPLC to afford a racemic mixture of(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanol(5.80 mg, 63% yield) as a white solid. LC-MS m/z 470.1 [M+H]⁺. ¹H NMR(CDCl₃ 400 MHz): δ 8.68 (s, 1H), 8.01 (s, 1H), 7.93-7.81 (m, 2H), 6.11(d, J=8.0 Hz, 1H), 5.38 (dd, J=5.2 Hz, J=14.4 Hz, 1H), 4.74 (s, 2H),4.38-4.30 (m, 1H), 4.25-4.15 (m, 1H), 3.86-3.76 (m, 1H), 3.10 (s, 3H),2.56-2.47 (m, 1H), 1.32 (d, J=6.8 Hz, 3H), 1.08 (d, J=6.8 Hz, 3H).

Example 52-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide

To a solution of ethyl2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate(20 mg, 0.04 mmol, prepared according to example 3) in MeOH (3 mL), H₂O(1 mL) was added NaOH (4.7 mg, 0.12 mmol). The mixture was stirred at rtovernight. The mixture was diluted with water (10 mL), acidified with 1NHCl to pH=3-4 and extracted with EtOAc (3×10 mL). The combined organiclayers were washed with brine (10 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated to afford2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylicacid (20 mg, 100% yield) as a yellow solid, which was used for the nextstep without further purification.

To a solution of2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylicacid (50 mg, 0.10 mmol) in DMF (10 mL) was added HATU (59 mg, 0.16mmol), NH₄CI (100 mg, 1.97 mmol), Et₃N (30 mg, 0.31 mmol) under N₂. Themixture was stirred at rt for 2 h. The mixture was diluted with water(15 mL) and extracted with EtOAc (3×15 mL). The combined organic layerswere washed with brine (15 mL), dried over anhydrous Na₂SO₄, filtered,concentrated and purified by basic preparative HPLC to afford a racemicmixture of2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide(13.4 mg, 27% yield) as a white solid. LC-MS m/z 483.1 [M+H]⁺. ¹H NMR(CDCl₃ 400 MHz): δ 8.77 (s, 1H), 8.02 (s, 1H), 7.92-7.83 (m, 2H), 6.12(d, J=8.4 Hz, 1H), 8.78 (brs, 2H), 5.48-5.38 (m, 1H), 4.41-4.34 (m, 1H),4.25-4.12 (m, 1H), 3.87-3.77 (m, 1H), 3.10 (s, 3H), 2.52 (brs, 1H), 1.34(d, J=6.8 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H).

Example 6(R)-1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanoneand(S)-1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone

Step 1

To a 50 mL three-necked flask containing (R)-2-tert-butyl 8-methyl1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2,8(1H)-dicarboxylate(250 mg, 0.554 mmol, from preparation 2) in DCM (5 mL) was added DIBAL-H(1.70 mL, 1.67 mmol, 1.0 M in toluene) dropwise at −78° C. under N₂. Themixture was stirred at −78° C. for 3 h. The reaction was quenched withsat. aq. ammonium chloride (10 mL) at −78° C. The aqueous layer wasextracted with EtOAc (3×20 mL). The combined organic layers were washedwith water (15 mL) and brine, and then dried over anhydrous Na₂SO₄. Themixture was filtered and the filtrate was evaporated under reducedpressure. The residue was purified by column chromatography on silicagel eluting with PE:EtOAc 8:1˜2:1 to give (R)-tert-butyl8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate(175 mg, 74.1% yield) as a white solid.

Step 2

To a 50 mL round-bottomed flask containing (R)-tert-butyl8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate(236 mg, 0.558 mmol) in CH₂Cl₂ (5 mL) was added Et₃N (169 mg, 1.67 mmol)and AcCl (87 mg, 1.12 mmol) under N₂. The mixture was stirred at rt for10 min. The reaction was quenched with water (20 mL). The aqueous layerwas extracted with CH₂Cl₂ (3×20 mL). The combined organic layers werewashed with water (25 mL) and brine, and then dried over anhydrousNa₂SO₄. The mixture was filtered and the filtrate was evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel eluting with PE:EtOAc 8:1-4:1 to give (R)-tert-butyl8-(acetoxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate(210 mg, 81.1% yield) as a yellow solid.

Step 3

TFA (1 mL) was added dropwise to a solution containing (R)-tert-butyl8-(acetoxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate(210 mg, 0.452 mmol) in DCM (5 mL) at rt. The mixture was stirred at rtfor 2 h. TLC showed compound 3 was consumed completely. The solventswere removed under reduced pressure at 30° C. and then DCM (10 mL) wasadded. The mixture was neutralized by sat. NaHCO₃ solution to pH=8. Themixture was extracted with DCM (3×20 mL) and the combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated under vacuumto afford(R)-(1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methylacetate (160 mg, 97.1% yield) as a white solid, which was used directlyfor the next step without further purification.

Step 4

To a solution of(R)-(1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methylacetate (160 mg, 0.456 mmol) in ^(i)PrOH (4 mL) and DCM (2 mL) was added1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (306 mg, 1.37mmol) and DIEA (353 mg, 2.74 mmol). The mixture was stirred at 60° C.overnight. Water (5 mL) was added to the mixture and the aqueous layerwas extracted with EtOAc (2×10 mL). The combined organic layers werewashed with water (2×10 mL) and brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by preparative TLC to afford(R)-(2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methylacetate (150 mg, 44.4% yield) as a yellow oil.

Step 5

To a solution of(R)-(2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methylacetate (100 mg, 0.181 mmol) in THF (2 mL) and H₂O (2 mL) was added LiOH(38 mg, 0.905 mmol). The mixture was stirred at rt for 10 min. Themixture was extracted with EtOAc (3×10 mL). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by basic preparativeHPLC to afford the crude product (53.1 mg, 55.9% yield). The crudeproduct was separated by SFC to afford(R)-1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone(32.90 mg, isomer 1) as a white solid and(S)-1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone(16.90 mg, isomer 2) as a white solid. Isomer 1:(R)-1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone.Analytical chiral HPLC: t_(R)=7.280 min in 15 min chromatography(Method: AS-H_5_5_40_2.35 ML). LC-MS m/z 512.1 [M+H]⁺. ¹H NMR (CD₃OD 400MHz): δ 9.00 (s, 1H), 8.23 (s, 1H), 7.95 (s, 1H), 6.11-6.07 (m, 1H),5.49-5.32 (m, 1H), 5.10 (s, 2H), 4.54 (dd, J=3.6 Hz and 12.4 Hz, 1H),4.24 (dt, J=4.8 and 12.0 Hz, 1H), 3.98-3.90 (m, 1H), 3.25 (s, 3H),2.61-2.57 (m, 1H), 2.56 (s, 3H), 1.29 (d, J=6.8 Hz, 3H), 1.07 (d, J=6.8Hz, 3H). Isomer 2:(S)-1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanoneAnalytical chiral HPLC: t_(R)=8.485 min in 15 min chromatography(Method: AS-H_5_5_40_2.35 ML). LC-MS m/z 512.1 [M+H]⁺. ¹H NMR (CD₃OD 400MHz): δ 9.00 (s, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 6.12-6.08 (m, 1H),5.48-5.31 (m, 1H), 5.11 (s, 2H), 4.56 (dd, J=3.6 Hz and 12.4 Hz, 1H),4.24 (dt, J=4.8 and 12.0 Hz, 1H), 3.98-3.91 (m, 1H), 3.26 (s, 3H),2.61-2.58 (m, 1H), 2.56 (s, 3H), 1.29 (d, J=6.0 Hz, 3H), 1.07 (d, J=6.8Hz, 3H).

Example 7(R)-2-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-oland(S)-2-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol

(R)-(2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methylacetate (150 mg, 0.271 mmol, partially racemized) was added MeMgCl (3.0M in toluene, 0.50 mL, 1.36 mmol) at −10° C. The mixture was stirred at−10° C. for 3 h. Sat. NH₄Cl solution (10 mL) was added at −10° C. andthe mixture was filtered. The aqueous layer was extracted with DCM (3×20mL). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by preparative TLC to give the racemic mixture(65.0 mg, 45.5% yield) as a white solid. The racemic mixture waspurified by SFC separation to give(R)-2-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol(16.20 mg, isomer 1) and(S)-2-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol(9.10 mg, isomer 2) as white solids.

Isomer 1:(R)-2-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol.Analytical chiral HPLC: t_(R)=8.600 min in 15 min chromatography(Method: OD-H_3_5_40_2.35 ML). LC-MS MS (ESI) m/z 528.2 [M+H]⁺. ¹H NMR(CD₃OD 400 MHz): δ 8.87 (s, 1H), 8.20 (s, 1H), 7.93 (s, 1H), 6.02 (d,J=8.0 Hz, 1H), 5.31 (dd, J=5.2 and 14.4 Hz, 1H), 5.09 (s, 2H), 4.50-4.46(m, 1H), 4.23-4.16 (m, 1H), 3.90-3.83 (m, 1H), 3.24 (s, 3H), 2.59-2.51(m, 1H), 1.59 (s, 6H), 1.26 (d, J=6.8 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H).

Isomer 1 can be recrystallized as a hydrochloric acid salt according tofollowing procedure:

To a solution of(R)-2-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol(52 mg, 0.1 mmol) in methanol (2 mL) was added acetyl chloride (7 μL,0.1 mmol) and the mixture was stirred at rt for 4 h. Methanol wasremoved under reduced pressure. The crude resultant was dissolved intomixture of acetone and EtOAc (2.5 mL/2.5 mL) followed by filtration. Tothe filtrate, hexanes (0.4 mL) were slowly added with intermittentheating. Leave the solution stay at rt until crystals form. The crystalwas collected by filtration. m.p. 176-179° C. LC-MS m/z 528 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.95 (s, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 6.28(d, J=8.0 Hz, 1H), 5.43 (dd, J₁=14.4 Hz, J₂=4.8 Hz, 1H), 5.15 (s, 2H),4.70 (dd, J₁=12.8 Hz, J₂=3.6 Hz, 1H), 4.34 (td, J₁=12.0 Hz, J₂=4.8 Hz,1H), 3.92 (dddd, J₁=14.4 Hz, J₂=12.8 Hz, J₃=4.8 Hz, 1H), 3.26 (s, 3H),2.70-2.62 (m, 1H), 1.60 (s, 6H), 1.31 (d, J=6.8 Hz, 3H), 1.13 (d, J=6.8Hz, 3H).

Isomer 2:(S)-2-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol.Analytical chiral HPLC: t_(R)=6.680 min in 15 min chromatography(Method: OD-H_3_5_40_2.35 ML). LC-MS MS (ESI) m/z 528.2 [M+H]⁺. ¹H NMR(CD₃OD 400 MHz): 8.87 (s, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 6.03 (d,J=8.0 Hz, 1H), 5.31 (dd, J=4.4 and 14.0 Hz, 1H), 5.09 (s, 2H), 4.51-4.47(m, 1H), 4.23-4.16 (m, 1H), 3.91-3.83 (m, 1H), 3.25 (s, 3H), 2.60-2.51(m, 1H), 1.59 (s, 6H), 1.26 (d, J=6.8 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H).

Alternatively, a racemic mixture of2-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-olwere prepared by following method.

(rac)-2-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol

(R)-methyl-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(224 mg, 0.639 mmol) and2-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol (192 mg, 0.799mmol) were combined in a small vial and azeotroped with benzene toremove any residual water. A mixture of dioxane (1 mL) and iPr₂NEt (0.22mL, 1.28 mmol) was degassed with N₂ for 10 minutes. This mixture wasthen added to the reaction vial and sealed with a Teflon® coated capwhich was then wrapped with Teflon® tape. The resulting suspension wasthen placed in a 165° C. silicone oil bath at which point the mixturebecame homogeneous. The resulting solution stirred at 165° C. for 21 h.After the solvents were removed by rotovap, the mixture was purifiedusing ISCO FCC, eluting with 50% EtOAc in Hexanes to obtain 219 mg of(R)-methyl-2-(5-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylateas a white solid (62% yield, 40% ee).

LC-MS MS (ESI) m/z 556.0 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz): δ 8.88 (s,1H), 8.28 (s, 1H), 7.98 (s, 1H), 6.05 (d, J=8.0 Hz, 1H), 5.32 (dd, J=4.8and 14.0 Hz, 1H), 4.53 (dd, J=3.2 and 12 Hz, 1H), 4.27-4.20 (m, 1H),3.95 (s, 3H), 3.90-3.83 (m, 1H), 3.41 (s, 3H), 2.61-2.52 (m, 1H), 1.59(s, 6H), 1.27 (d, J=6.8 Hz, 3H), 1.06 (d, J=6.8 Hz, 3H).

To a solution of(R)-methyl-2-(5-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(109 mg, 0.196 mmol) in DCM (4 mL) was added a solution of DIBAL-H inDCM (0.98 mL of a 1.0 M solution, 0.98 mmol) dropwise at −78° C. Thereaction slowly warmed to −10° C. over approximately 1 h, at which point1 mL of MeOH was added to quench the excess DIBAL-H. Sat. aq. Rochellesalt (potassium sodium tartrate (KNaC₄H₄O₆)) solution (5 mL) and DCM (5mL) were added and the mixture stirred vigorously for 15 min. The DCMlayer was separated and the aqueous layer was extracted with DCM (2×5mL). The DCM layers were combined, dried using Na₂SO₄ and evaporated togive the crude product. Purification using ISCO FCC eluting with 70%EtOAc in Hexanes gave 71 mg of2-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-olas a racemic mixture (69%). LC-MS MS (ESI) m/z 528.25 [M+H]⁺. ¹H NMR(CDCl₃, 400 MHz): δ 8.72 (s, 1H), 8.05 (s, 1H), 7.80 (s, 1H), 6.01 (d,J=7.6 Hz, 1H), 5.27 (d, J=4.4 and 14.0 Hz, 1H), 5.00-4.86 (m, 2H),4.26-4.08 (m, 2H), 3.74-3.67 (m, 1H), 3.15 (s, 3H), 3.15-3.10 (m, 1H),2.47-2.40 (m, 1H), 1.96 (b, 1H), 1.59 (s, 6H), 1.23 (d, J=6.8 Hz, 3H),1.10 (d, J=6.8 Hz, 3H).

2-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol was preparedas following:

To a 1.0 M solution of TiCl₄ in toluene (6.67 mL, 6.67 mmol) was added a1.6 M solution of MeLi in Et₂O (4.18 mL, 6.69 mmol) dropwise a −78° C.(dry ice/acetone bath). The resulting dark solution stirred at −78° C.for 30 minutes. A solution of1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (500 mg, 2.23mmol) in Et₂O (3 mL) was added dropwise at −78° C. The reaction wasslowly allowed to warm to rt in the dewar over a 15 h period. TLCanalysis showed complete conversion to the more polar tertiary alcoholproduct. The mixture was then cooled to 0° C. and quenched with sat. aq.NH₄Cl (10 mL) followed by EtOAc (10 mL) for the workup. The EtOAc layerwas separated and the aqueous layer was extracted with EtOAc (2×10 mL).The EtOAc layers were combined, dried using Na₂SO₄ and evaporated togive the crude product. Purification using ISCO FCC eluting with 20%EtOAc in Hexanes gave 459 mg of2-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol (86% yield) asa colorless oil. LC-MS MS (ESI) m/z 241.12 [M+H]+. ¹H NMR (CDCl₃, 400MHz): δ 9.05 (s, 1H), 1.99 (s, 1H), 1.67 (s, 6H).

Example 81-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanol(4 isomers)

To a solution of (R)-methyl1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(220 mg, 0.627 mmol) in ^(i)PrOH (4 mL) and DCM (2 mL) was added1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (421 mg, 1.88mmol) and DIEA (485 mg, 3.76 mmol). The mixture was stirred at 60° C.overnight. Water (5 mL) was added to the mixture and the aqueous layerwas extracted with EtOAc (2×10 mL). The combined organic layers werewashed with water (2×10 mL) and brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by preparative TLC to afford (R)-methyl2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(150 mg, 44.4% yield) as a yellow solid.

To a 50 mL three-necked flask containing (R)-methyl2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(150 mg, 0.278 mmol) in DCM (3 mL) was added DIBAL-H (1.10 mL, 1.11mmol, 1.0 M in toluene) dropwise at −78° C. under N₂. The mixture wasstirred at −78° C. for 3 h. Sat. NH₄Cl solution (10 mL) was added at−78° C. and the mixture was filtered. The aqueous layer was extractedwith DCM (3×20 mL). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by preparative TLC to give theracemic mixture (81.0 mg, 56.7% yield) as a white solid. The racemicmixture was purified by SFC separation to give isomer 1 (10.60 mg, 47.1%yield) as a white solid, isomer 2 (7.10 mg, 31.6% yield) as a whitesolid, isomer 3 (4.70 mg, 26.1% yield) as a white solid and isomer 4(6.00 mg, 33.3% yield) as a white solid.

Isomer 1

Analytical chiral HPLC: t_(R)=8.397 min in 15 min chromatography(Method: OD-H_5_5_40_2.35 ML). LC-MS MS (ESI) m/z 514.1 [M+H]⁺. ¹H NMR(CD₃OD 400 MHz): δ 8.89 (s, 1H), 8.20 (s, 1H), 7.93 (s, 1H), 6.03 (d,J=8.0 Hz, 1H), 5.32 (dd, J=4.4 and 14.4 Hz, 1H), 5.11-5.08 (m, 3H),4.50-4.46 (m, 1H), 4.28-4.16 (m, 1H), 3.90-3.83 (m, 1H), 3.24 (s, 3H),2.72-2.39 (m, 1H), 1.42 (d, J=6.4 Hz, 3H), 1.26 (d, J=6.8 Hz, 3H), 1.04(d, J=6.8 Hz, 3H).

Isomer 2

Analytical chiral HPLC: t_(R)=6.700 min in 15 min chromatography(Method: AS-H_5_5_40_2.35 ML). LC-MS MS (ESI) m/z 514.1 [M+H]⁺. ¹H NMR(CD₃OD 400 MHz): δ 8.89 (s, 1H), 8.21 (s, 1H), 7.93 (s, 1H), 6.03 (d,J=8.0 Hz, 1H), 5.32 (dd, J=4.4 and 14.4 Hz, 1H), 5.11-5.08 (m, 3H),4.50-4.46 (m, 1H), 4.23-4.16 (m, 1H), 3.95-3.79 (m, 1H), 3.25 (s, 3H),2.59-2.51 (m, 1H), 1.42 (d, J=6.0 Hz, 3H), 1.26 (d, J=6.4 Hz, 3H), 1.04(d, J=6.4 Hz, 3H).

Isomer 3

Analytical chiral HPLC: t_(R)=7.666 min in 15 min chromatography(Method: AS-H_5_5_40_2.35 ML). LC-MS MS (ESI) m/z 514.2 [M+H]⁺. ¹H NMR(CD₃OD 400 MHz): δ 8.89 (s, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 6.03 (d,J=8.0 Hz, 1H), 5.32 (dd, J=4.0 and 14.0 Hz, 1H), 5.11-5.08 (m, 3H),4.51-4.47 (m, 1H), 4.24-4.15 (m, 1H), 3.91-3.84 (m, 1H), 3.25 (s, 3H),2.61-2.43 (m, 1H), 1.42 (d, J=6.0 Hz, 3H), 1.26 (d, J=6.8 Hz, 3H), 1.05(d, J=6.8 Hz, 3H).

Isomer 4

Analytical chiral HPLC: t_(R)=9.621 min in 15 min chromatography(Method: OD-H_5_5_40_2.35 ML). LC-MS MS (ESI) m/z 514.1 [M+H]⁺. ¹H NMR(CD₃OD 400 MHz): δ 8.89 (s, 1H), 8.21 (s, 1H), 7.93 (s, 1H), 6.03 (d,J=8.0 Hz, 1H), 5.32 (dd, J=4.0 and 14.0 Hz, 1H), 5.11-5.08 (m, 3H),4.50-4.23 (m, 1H), 4.23-4.15 (m, 1H), 3.91-3.80 (m, 1H), 3.25 (s, 3H),2.59-2.51 (m, 1H), 1.42 (d, J=6.4 Hz, 3H), 1.26 (d, J=6.8 Hz, 3H), 1.05(d, J=6.8 Hz, 3H).

Example 9(R)-1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-1-oneand(S)-1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-1-one

The title compounds were prepared following procedure analogous to thosedescribed in Example 6 by using1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)propan-1-one in stead of1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone.

Isomer 1:(R)-1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-1-one.Analytical chiral HPLC: t_(R)=6.87 min in 15 min chromatography (Method:OJ-H_3_5_40_2.5 ML). LC-MS m/z 526.1 [M+H]⁺. ¹H NMR (CD₃OD 400 MHz): δ8.94 (s, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 6.17-6.02 (m, 1H), 5.43-5.32(m, 1H), 5.11 (s, 2H), 4.54 (dd, J=4.0 and 12.0 Hz, 1H), 4.24 (dt, J=4.8and 12.0 Hz, 1H), 3.98-3.90 (m, 1H), 3.27 (s, 3H), 2.93 (q, J=6.8 Hz,2H), 2.61-2.55 (m, 1H), 1.29 (d, J=6.8 Hz, 3H), 1.15 (t, J=7.2 Hz, 3H),1.07 (d, J=6.8 Hz, 3H).

Isomer 2:(S)-1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-1-one.Analytical chiral HPLC: t_(R)=8.40 min in 15 min chromatography (Method:OJ-H_3_5_40_2.5 ML). LC-MS m/z 526.1 [M+H]⁺. ¹H NMR (CD₃OD 400 MHz): δ8.93 (s, 1H), 8.21 (s, 1H), 7.93 (s, 1H), 6.15-6.01 (m, 1H), 5.47-5.31(m, 1H), 5.09 (s, 2H), 4.53 (dd, J=4.0 and 12.0 Hz, 1H), 4.24 (dt, J=4.8and 12.0 Hz, 1H), 3.97-3.90 (m, 1H), 3.24 (s, 3H), 2.92 (q, J=6.8 Hz,2H), 2.60-2.55 (m, 1H), 1.28 (d, J=6.8 Hz, 3H), 1.14 (t, J=7.2 Hz, 3H),1.07 (d, J=6.8 Hz, 3H).

Example 101-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-1-ol(4 isomers)

The title compounds were prepared following procedure analogous to thosedescribed in Example 8 by using1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)propan-1-one in stead of1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone.

Isomer 1: a white solid. Analytical chiral HPLC: t_(R)=6.529 min in 15min chromatography (Method: OD-H_3_5_40_2.35 ML). LC-MS m/z 528.2[M+H]⁺. ¹H NMR (CDCl₃ 400 MHz): δ 8.81 (s, 1H), 8.13 (s, 1H), 7.88 (s,1H), 6.10 (d, J=7.6 Hz, 1H), 5.38-5.34 (m, 1H), 5.05-5.02 (m, 2H),4.98-4.90 (m, 1H), 4.34-4.30 (m, 1H), 4.21-4.17 (m, 1H), 3.82-3.74 (m,1H), 3.23 (s, 3H), 3.06 (t, J=7.2 Hz, 1H), 2.52-2.50 (m, 1H), 1.94-1.93(m, 1H), 1.80-1.76 (m, 2H), 1.31 (d, J=6.8 Hz, 3H), 1.08 (d, J=6.8 Hz,3H), 0.99 (t, J=7.2 Hz, 3H).

Isomer 2: a white solid. Analytical chiral HPLC: t_(R)=7.502 min in 15min chromatography (Method: OD-H_3_5_40_2.35 ML). LC-MS m/z 528.2[M+H]⁺. ¹H NMR (CDCl₃ 400 MHz): δ 8.82 (s, 1H), 8.13 (s, 1H), 7.88 (s,1H), 6.10 (d, J=7.6 Hz, 1H), 5.39-5.34 (m, 1H), 5.05-5.02 (m, 2H),4.98-4.90 (m, 1H), 4.34-4.30 (m, 1H), 4.21-4.16 (m, 1H), 3.82-3.74 (m,1H), 3.22 (s, 3H), 3.10 (t, J=6.8 Hz, 1H), 2.52-2.49 (m, 1H), 2.01-2.00(m, 1H), 1.80-1.75 (m, 2H), 1.30 (d, J=6.8 Hz, 3H), 1.08 (d, J=6.8 Hz,3H), 0.99 (t, J=7.2 Hz, 3H).

Isomer 3: a white solid. Analytical chiral HPLC: t_(R)=5.173 min in 15min chromatography (Method: OJ-H_3_5_40_2.35 ML). LC-MS m/z 528.2[M+H]⁺. ¹H NMR (CDCl₃ 400 MHz): δ 8.81 (s, 1H), 8.13 (s, 1H), 7.88 (s,1H), 6.10 (d, J=7.6 Hz, 1H), 5.38-5.34 (m, 1H), 5.05-5.02 (m, 2H),4.98-4.90 (m, 1H), 4.34-4.30 (m, 1H), 4.21-4.17 (m, 1H), 3.82-3.76 (m,1H), 3.23 (s, 3H), 3.07 (t, J=6.8 Hz, 1H), 2.52-2.50 (m, 1H), 1.94-1.93(m, 1H), 1.80-1.75 (m, 2H), 1.31 (d, J=6.8 Hz, 3H), 1.08 (d, J=6.8 Hz,3H), 0.99 (t, J=7.2 Hz, 3H).

Isomer 4: a white solid. Analytical chiral HPLC: t_(R)=5.817 min in 15min chromatography (Method: OJ-H_3_5_40_2.35 ML). LC-MS m/z 528.2[M+H]⁺. ¹H NMR (CDCl₃ 400 MHz): δ 8.81 (s, 1H), 8.13 (s, 1H), 7.88 (s,1H), 6.10 (d, J=8.0 Hz, 1H), 5.38-5.35 (m, 1H), 5.05-5.04 (m, 2H),4.98-4.90 (m, 1H), 4.34-4.30 (m, 1H), 4.21-4.18 (m, 1H), 3.81-3.76 (m,1H), 3.23 (s, 3H), 3.06 (t, J=6.4 Hz, 1H), 2.52-2.50 (m, 1H), 1.94-1.93(m, 1H), 1.81-1.75 (m, 2H), 1.31 (d, J=6.8 Hz, 3H), 1.08 (d, J=6.8 Hz,3H), 0.99 (t, J=7.2 Hz, 3H).

Example 11(R)-1-(2-((R)-8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)butan-1-oland(S)-1-(2-((R)-8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)butan-1-ol

The title compounds were prepared following procedure analogous to thosedescribed in Example 8 by using1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)butan-1-one in stead of1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone.

Isomer 1: Analytical chiral HPLC: t_(R)=8.450 min in 15 minchromatography (Method: OD-H_3_5_40_2.35 ML). LC-MS MS (ESI) m/z 542.1[M+H]⁺. ¹H NMR (CD₃OD 400 MHz): δ 8.87 (s, 1H), 8.26 (s, 1H), 7.98 (s,1H), 6.06 (d, J=8.0 Hz, 1H), 5.36-5.33 (m, 1H), 5.14 (s, 2H), 4.54-4.51(m, 1H), 4.27-4.20 (m, 1H), 3.94-3.86 (m, 1H), 3.29 (s, 3H), 2.60-2.52(m, 1H), 1.78-1.71 (m, 1H), 1.60-1.49 (m, 2H), 1.43-1.26 (m, 5H), 1.08(d, J=6.8 Hz, 3H), 0.96 (t, J=6.8 Hz, 3H).

Isomer 2: Analytical chiral HPLC: t_(R)=10.264 min in 15 minchromatography (Method: OD-H_3_5_40_2.35 ML). LC-MS MS (ESI) m/z 542.1[M+H]⁺. ¹H NMR (CD₃OD 400 MHz): δ 8.87 (s, 1H), 8.26 (s, 1H), 7.98 (s,1H), 6.06 (d, J=8.0 Hz, 1H), 5.36-5.33 (m, 1H), 5.14 (s, 2H), 4.54-4.51(m, 1H), 4.27-4.20 (m, 1H), 3.94-3.86 (m, 1H), 3.29 (s, 3H), 2.60-2.52(m, 1H), 1.78-1.71 (m, 1H), 1.60-1.49 (m, 2H), 1.43-1.26 (m, 5H), 1.08(d, J=6.8 Hz, 3H), 0.96 (t, J=6.8 Hz, 3H).

Example 12 (R)-ethyl2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate

To a solution of(R)-(1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methanol(30 mg, 0.093 mmol) in CH₂Cl₂ (0.5 mL) and ^(i)PrOH (0.5 mL) was addedethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (36 mg, 0.14mmol) and DIEA (36 mg, 0.28 mmol). The mixture was stirred at 70° C.overnight. The mixture was concentrated under reduced pressure. Water (5mL) was added to the mixture and the aqueous layer was extracted withEtOAc (3×10 mL). The combined organic layers were washed with water andbrine, dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by preparative TLC to afford (R)-ethyl2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate(42.0 mg, 83.7% yield) as a white solid. Analytical chiral HPLC:t_(R)=9.927 min in 15 min chromatography, 96.74% ee (Method:OD-H_5_5_40_2.35 ML). LC-MS MS (ESI) m/z 542.1 [M+H]⁺. ¹H NMR (CD₃OD 300MHz): δ 8.96 (s, 1H), 8.12 (s, 1H), 7.85 (s, 1H), 6.12-6.00 (m, 1H),5.45-5.29 (m, 1H), 5.01 (s, 2H), 4.51-4.47 (m, 1H), 4.33-4.18 (m, 3H),3.91 (t, J=10.8 Hz, 1H), 3.18 (s, 3H), 2.63-2.47 (m, 1H), 1.35-1.26 (m,6H), 1.05 (d, J=6.6 Hz, 3H).

Example 13(R)-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanoland(S)-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanol

To a solution of (R)-methyl1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(80 mg, 0.228 mmol) in ^(i)PrOH (2 mL) and DCM (1 mL) was added ethyl2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (174 mg, 0.684mmol) and DIEA (177 mg, 1.37 mmol). The mixture was stirred at 60° C.overnight. Water (5 mL) was added to the mixture and the aqueous layerwas extracted with EtOAc (2×10 mL). The combined organic layers werewashed with water (2×10 mL) and brine, dried over anhydrous Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bypreparative TLC to afford (R)-methyl2-(5-(ethoxycarbonyl)-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(75 mg, 57.8% yield) as a yellow solid.

To a solution of (R)-methyl2-(5-(ethoxycarbonyl)-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(75 mg, 0.132 mmol) in DCM (3 mL) was added DIBAL-H (1M in toluene, 0.50mL, 0.528 mmol) at −78° C. The mixture was stirred at −78° C. for 3 h.Sat. NH₄Cl solution (10 mL) was added at −78° C. and the mixture wasfiltered. The aqueous layer was extracted with DCM (3×20 mL). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by preparative TLC to give the racemic mixture (56.0 mg,85.1% yield) as a white solid. The racemic mixture was separated by SFCseparation to give(R)-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanol(38.10 mg, isomer 1) and(S)-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanol(11.90 mg, isomer 2) as white solids.

Isomer 1:(R)-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanol.Analytical chiral HPLC: t_(R)=10.281 min in 15 min chromatography(Method: AD-H_5_5_40_2.35 ML). LC-MS MS (ESI) m/z 500.1 [M+H]⁺. ¹H NMR(CD₃OD 400 MHz): δ 8.73 (s, 1H), 8.20 (s, 1H), 7.93 (s, 1H), 6.04 (d,J=8.0 Hz, 1H), 5.33 (dd, J=4.4 and 14.0 Hz, 1H), 5.09 (s, 2H), 4.63 (s,2H), 4.50-4.46 (m, 1H), 4.28-4.06 (m, 1H), 3.91-3.83 (m, 1H), 3.24 (s,3H), 2.59-2.47 (m, 1H), 1.26 (d, J=6.8 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H).

Isomer 2:(S)-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanol.Analytical chiral HPLC: t_(R)=8.340 min in 15 min chromatography(Method: AD-H_5_5_40_2.35 ML). LC-MS MS (ESI) m/z 500.1 [M+H]⁺. ¹H NMR(CD₃OD 400 MHz): δ 8.73 (s, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 6.04 (d,J=8.4 Hz, 1H), 5.33 (dd, J=4.8 and 14.4 Hz, 1H), 5.09 (s, 2H), 4.63 (s,2H), 4.52-4.45 (m, 1H), 4.24-4.17 (m, 1H), 3.91-3.84 (m, 1H), 3.25 (s,3H), 2.68-2.46 (m, 1H), 1.26 (d, J=6.8 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H).

Example 14(R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylicacid and(S)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylicacid

The mixture of(R)-(1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methylacetate (284 mg, 0.8 mmol), ethyl2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (296 mg, 1.2 mmol,1.5 eq.) and DIEA (310 mg, 2.4 mmol, 3 eq.) in CH₂Cl₂/i-PrOH (3 mL/3 mL)was stirred at 80° C. for 16 h. TLC showed compound was consumedcompletely PE:EtOAc=1:1. The solvents were removed under vacuum and theresidue was dissolved in EtOAc (10 mL). Water (10 mL) was added to themixture. The mixture was extracted with EtOAc (10 mL×3). The organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by column chromatography on silica geleluting with PE:EtOAc 5:1 to give (R)-ethyl2-(8-(acetoxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate(0.41 g, 87% yield) as a pale yellow solid.

(R)-ethyl2-(8-(acetoxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate(0.1 g, 0.17 mmol) in MeOH/H₂O (5 mL/1 mL) was added LiOH H₂O (86 mg, 2mmol). The mixture was stirred at rt for 16 h. The excess methanol wasremoved by vacuum at 40° C. Water (5 ml) was added and the mixture wasneutralized by 1N HCl at 0° C. slowly to pH=6. The aqueous layer wasextracted with CH₂Cl₂ (4×10 mL). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated under vacuum to givecrude product. The crude product was purified by SFC to afford(R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylicacid (34.50 mg, 40% yield, isomer 1) as a white solid and(S)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylicacid (6.40 mg, 7% yield, isomer 2) as white solid.

Isomer 1:(R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylicacid. Analytical chiral HPLC: t_(R)=6.474 min in 15 min chromatography(Method: OJ-H_3_5_40_2.35 ML). LC-MS MS (ESI) m/z 514.0 [M+H]⁺. ¹H NMR(CD₃OD 400 MHz): 9.05 (s, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 6.20-6.15 (m,1H), 5.50-5.35 (m, 1H), 5.08 (s, 2H), 4.60-4.50 (m, 1H), 4.35-4.20 (m,1H), 4.03-3.89 (m, 1H), 3.25 (s, 3H), 2.70-2.53 (m, 1H), 1.30 (d, J=6.8Hz, 3H), 1.08 (d, J=6.8 Hz, 3H).

Isomer 2:(S)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylicacid. Analytical chiral HPLC: t_(R)=8.468 min in 15 min chromatography(Method: OJ-H_3_5_40_2.35 ML). LC-MS MS (ESI) m/z 514.0 [M+H]⁺. ¹H NMR(CD₃OD 400 MHz): 9.02 (s, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 6.20-6.15 (m,1H), 5.50-5.35 (m, 1H), 5.12 (s, 2H), 4.60-4.50 (m, 1H), 4.35-4.20 (m,1H), 4.03-3.89 (m, 1H), 3.28 (s, 3H), 2.70-2.50 (m, 1H), 1.30 (d, J=6.8Hz, 3H), 1.08 (d, J=6.8 Hz, 3H).

Example 15(R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamideand(S)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide

To a solution of(R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylicacid (100 mg, 0.19 mmol, partially racemized) in DMF (2 mL) was addedHATU (97 mg, 0.25 mmol) and Et₃N (52 mg, 0.51 mmol). The mixture wasstirred at rt for 1 h. NH₄Cl (19 mg, 0.34 mmol) was added in oneportion. The mixture was stirred at rt for 16 h. Water (10 mL) was addedand the aqueous layer was extracted with EtOAc (4×10 mL). The combinedorganic layers were washed with water (3×10 mL) and brine, dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by preparative TLC and SFC separation to afford(R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide(55.2 mg, 56.7% yield, isomer 1) as a white solid and(S)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide(10.5 mg, 10.8% yield, isomer 2) as white solid.

Isomer 1:(R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide.Analytical chiral HPLC: t_(R)=6.084 min in 15 min chromatography(Method: OJ-H_3_5_40_2.35 ML). LC-MS MS (ESI) m/z 513.0 [M+H]⁺. ¹H NMR(CD₃OD 400 MHz): δ 8.71 (s, 1H), 8.25 (s, 1H), 7.97 (s, 1H), 6.13-6.01(m, 1H), 5.45-5.30 (m, 1H), 5.13 (s, 2H), 4.59-4.50 (m, 1H), 4.31-4.18(m, 1H), 4.00-3.86 (m, 1H), 3.27 (s, 3H), 2.65-2.50 (m, 1H), 1.28 (d,J=6.8 Hz, 3H), 1.06 (d, J=6.8 Hz, 3H).

Isomer 2:(S)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide.

Analytical chiral HPLC: t_(R)=7.218 min in 15 min chromatography(Method: OJ-H_3_5_40_2.35 ML). LC-MS MS (ESI) m/z 513.1 [M+H]⁺. ¹H NMR(CD₃OD 400 MHz): δ 8.71 (s, 1H), 8.25 (s, 1H), 7.97 (s, 1H), 6.13-6.02(m, 1H), 5.45-5.30 (m, 1H), 5.12 (s, 2H), 4.60-4.50 (m, 1H), 4.32-4.18(m, 1H), 4.00-3.86 (m, 1H), 3.28 (s, 3H), 2.65-2.50 (m, 1H), 1.28 (d,J=6.8 Hz, 3H), 1.06 (d, J=6.8 Hz, 3H).

Example 16(R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-N-methyl-4-(trifluoromethyl)pyrimidine-5-carboxamideand(S)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-N-methyl-4-(trifluoromethyl)pyrimidine-5-carboxamide

The title compounds were prepared by a procedure analogous to thosedescribed in Example 15 by using methylamine hydrochloric acid saltinstead of ammonium chloride as a reagent.

Isomer 1:(R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-N-methyl-4-(trifluoromethyl)pyrimidine-5-carboxamide.Analytical chiral HPLC: t_(R)=6.355 min in 15 min chromatography(Method: AS-H_3_5_40_2.35 ML). LC-MS MS (ESI) m/z 548.9 [M+Na]⁺. ¹H NMR(CD₃OD 400 MHz): δ 8.68 (s, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 6.14-6.00(m, 1H), 5.45-5.30 (m, 1H), 5.13 (s, 2H), 4.60-4.50 (m, 1H), 4.30-4.18(m, 1H), 4.00-3.86 (m, 1H), 3.30 (s, 3H), 2.90 (s, 3H), 2.66-2.51 (m,1H), 1.31 (d, J=6.8 Hz, 3H), 1.15 (d, J=6.8 Hz, 3H).

Isomer 2:(S)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-N-methyl-4-(trifluoromethyl)pyrimidine-5-carboxamide.Analytical chiral HPLC: t_(R)=6.486 min in 15 min chromatography(Method: AS-H_3_5_40_2.35 ML). LC-MS MS (ESI) m/z 549.0 [M+Na]⁺. ¹H NMR(CD₃OD 400 MHz): δ 8.68 (s, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 6.14-6.00(m, 1H), 5.45-5.30 (m, 1H), 5.13 (s, 2H), 4.62-4.52 (m, 1H), 4.32-4.20(m, 1H), 4.02-3.87 (m, 1H), 3.30 (s, 3H), 2.91 (s, 3H), 2.67-2.51 (m,1H), 1.31 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.8 Hz, 3H).

Example 17(R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-N,N-dimethyl-4-(trifluoromethyl)pyrimidine-5-carboxamideand(S)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-N,N-dimethyl-4-(trifluoromethyl)pyrimidine-5-carboxamide

The title compounds were prepared by a procedure analogous to thosedescribed in Example 15 by using dimethylamine hydrochloric acid saltinstead of ammonium chloride as a reagent.

Isomer 1:(R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-N,N-dimethyl-4-(trifluoromethyl)pyrimidine-5-carboxamide.Analytical chiral HPLC: t_(R)=3.649 min in 8 min chromatography (Method:AS-H_S_3_5_40_3 ML). LC-MS MS (ESI) m/z 563.1 [M+Na]⁺. ¹H NMR (CD₃OD 400MHz): δ 8.62 (s, 1H), 8.23 (d, J=6.4 Hz, 1H), 7.95 (d, J=5.2 Hz, 1H),6.09-5.98 (m, 1H), 5.50-5.26 (m, 1H), 5.10 (d, J=4.4 Hz, 2H), 4.59-4.50(m, 1H), 4.32-4.20 (m, 1H), 4.03-3.87 (m, 1H), 3.30-3.25 (m, 3H), 3.11(s, 3H), 2.95 (s, 3H), 2.67-2.51 (m, 1H), 1.31 (d, J=6.8 Hz, 3H), 1.09(d, J=6.8 Hz, 3H).

Isomer 2:(S)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-N,N-dimethyl-4-(trifluoromethyl)pyrimidine-5-carboxamide.Analytical chiral HPLC: t_(R)=4.502 min in 8 min chromatography (Method:AS-H_S_3_5_40_3 ML). LC-MS MS (ESI) m/z 563.1 [M+Na]⁺. ¹H NMR (CD₃OD 400MHz): δ 8.62 (s, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 6.09-5.98 (m, 1H),5.49-5.28 (m, 1H), 5.13 (s, 2H), 4.59-4.50 (m, 1H), 4.33-4.20 (m, 1H),4.05-3.90 (m, 1H), 3.30 (s, 3H), 3.12 (s, 3H), 2.95 (s, 3H), 2.68-2.52(m, 1H), 1.32 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H).

Example 18(R)-(1-isopropyl-2-(4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methanol

To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (20.0 mg,0.092 mmol) in DCE (1 mL) and t-BuOH (1 mL) was added ZnCl₂ (1M indiethyl ether, 0.2 mL, 0.2 mmol) at 0° C. The mixture was stirred at 0°C. for 1 h. Then a solution of (R)-methyl1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(31 mg, 0.09 mmol) in DCE (1 mL) and t-BuOH (1 mL) was added to thereaction mixture via syringe over 1 min at 0° C. After addition, theresulting mixture was stirred at rt overnight. The reaction mixture wasconcentrated under vacuum. Water (5 mL) and EtOAc (5 mL) were added tothe mixture. The aqueous phase was extracted with EtOAc (3×10 mL). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby preparative TLC to afford (R)-methyl2-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(20 mg, 42.6% yield) as a white solid.

To a solution of (R)-methyl2-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(15 mg, 0.028 mmol) in methanol (4 mL) was added NaHCO₃ (25 mg, 0.29mmol). The mixture was stirred at 60° C. for 20 h. The mixture wasconcentrated under vacuum. Water (5 mL) and EtOAc (5 mL) were added tothe mixture. The aqueous phase was extracted with EtOAc (3×10 mL). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby preparative TLC to afford (R)-methyl1-isopropyl-2-(4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(13.0 mg, 87.2% yield) as a white solid.

To a solution of (R)-methyl1-isopropyl-2-(4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(15 mg, 0.028 mmol) in CH₂Cl₂ (2 mL) was added DIBAL H (1M in toluene,0.1 mL, 0.1 mmol) at −78° C. The mixture was stirred at −78° C. for 2 hand warmed to rt for 6 h. Sat. NH₄Cl solution (1 mL) was added and themixture was filtered. The filtrate was concentrated under vacuum. Water(5 mL) and EtOAc (5 mL) were added to the mixture. The aqueous layer wasextracted with EtOAc (3×5 mL). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by preparative TLC to afford(R)-(1-isopropyl-2-(4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methanol(3.50 mg, 24.6% yield) as a white solid. Analytical chiral HPLC:t_(R)=6.598 min in 15 min chromatography, 94.60% ee (Method:OD-H_3_5_40_2.35 ML). LC-MS MS (ESI) m/z 500.1 [M+H]⁺. ¹H NMR (CDCl₃ 300MHz): δ 8.31 (s, 1H), 8.12 (s, 1H), 7.86 (s, 1H), 6.02-5.98 (m, 1H),5.43-5.38 (m, 1H), 5.04-4.98 (m, 2H), 4.32-4.28 (m, 1H), 4.16 (dt, J=5.1and 12.0 Hz, 1H), 4.01 (s, 3H), 3.77-3.68 (m, 1H), 3.21 (s, 3H),3.11-3.06 (m, 1H), 2.50-2.47 (m, 1H), 1.30 (d, J=6.6 Hz, 3H), 1.07 (d,J=6.6 Hz, 3H).

Example 19(R)-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-methylpyrimidin-5-yl)methanol

A solution of methyl 2,4-dichloropyrimidine-5-carboxylate (27 mg, 0.13mmol) in dichloroethane/t-butanol (1:1, 2 mL) was cooled to 0° C. ZnCl₂solution (1.0 M in ether, 0.29 mL, 0.29 mmol, 2.2 eq.) was added. Afterstirring for 1 h, a solution of (R)-methyl1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(30 mg, 0.09 mmol) in dichloroethane/t-butanol (1:1, 2 mL) was addedslowly at 0° C. The mixture was stirred at rt overnight. Water (10 mL)was added and the mixture was extracted with EtOAc (10 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by preparative TLCto afford (R)-methyl2-(4-chloro-5-(methoxycarbonyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(34 mg, 77.3% yield) as a solid.

To a solution of (R)-methyl2-(4-chloro-5-(methoxycarbonyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(20 mg, 0.04 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (50mg, 0.4 mmol) in 5 mL of dioxane was added K₂CO₃ (54 mg, 0.4 mmol)followed by Pd(PPh₃)₄ (5 mg, 0.004 mmol) under N₂ with stirring. Themixture was refluxed for 2 h until the material was disappeared. Thereaction mixture was cooled to rt. The dioxane was removed under vacuum.Water (10 mL) was added and the mixture was extracted with EtOAc (10mL×3). The organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by preparative TLCto afford (R)-methyl1-isopropyl-2-(5-(methoxycarbonyl)-4-methylpyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(15 mg, 75% yield) as a colorless oil. LC-MS MS (ESI) m/z 502.1 [M+H]⁺.

To a solution of (R)-methyl1-isopropyl-2-(5-(methoxycarbonyl)-4-methylpyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(15 mg, 0.03 mmol) in toluene (2 mL) was added DIBAL H (1M in toluene,0.3 mL, 0.3 mmol) at −78° C. The mixture was stirred at −78° C. for 2 hand then rt for 30 mins. Sat. NH₄Cl solution (5 mL) was added slowly at0° C. and the mixture was filtered. The aqueous layer was extracted withEtOAc (3×10 mL). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by preparative TLC to afford(R)-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-methylpyrimidin-5-yl)methanol(1.6 mg, 12.3% yield) as a colorless oil. LC-MS MS (ESI) m/z 446.2[M+H]⁺. ¹H NMR (CD₃OD 400 MHz): δ 8.26 (s, 1H), 8.23 (s, 1H), 7.99 (s,1H), 6.00 (d, J=8.8 Hz, 1H), 5.17 (s, 2H), 4.90-4.79 (m, 1H), 4.67 (s,2H), 4.45-4.44 (m, 1H), 4.25-4.18 (m, 1H), 4.15-4.04 (m, 1H), 3.31 (s,3H), 2.58-2.49 (m, 1H), 2.45 (s, 3H), 1.25 (d, J=6.8 Hz, 3H), 1.12 (d,J=6.8 Hz, 3H).

Example 20(R)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-5-yl)methanoland(S)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-5-yl)methanol

To a solution of methyl 2,4-dichloropyrimidine-5-carboxylate (852 mg, 4mmol) and cyclopropylboronic acid (344 mg, 4 mmol) in THF (10 mL) wasadded K₃PO₄ (3.1 g, 12 mmol) followed by Pd(dppf)Cl₂ (292 mg, 0.4 mmol)under N₂. The mixture was refluxed for 4 h until the material wasdisappeared. The reaction mixture was cooled to rt. THF was removedunder vacuum. Water (20 mL) was added and the mixture was extracted withEtOAc (20 mL×3). The organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bypreparative TLC to afford methyl2-chloro-4-cyclopropylpyrimidine-5-carboxylate (220 mg, 26% yield) as awhite solid.

The mixture of (R)-methyl1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(77 mg, 0.22 mmol), methyl2-chloro-4-cyclopropylpyrimidine-5-carboxylate (57 mg, 0.26 mmol, 1.2eq.) and DIEA (172 mg, 1.3 mmol, 6 eq.) in CH₂Cl₂/i-PrOH (1 mL/1 mL) wasstirred at 120° C. for 16 h. TLC showed (R)-methyl1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylatewas consumed completely (PE:EtOAc=1:1). Water (10 mL) was added and themixture was extracted with EtOAc (10 mL×3). The organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by preparative TLC to afford (R)-methyl2-(4-cyclopropyl-5-(methoxycarbonyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(50 mg, 43% yield) as a colorless oil.

To a solution of (R)-methyl2-(4-cyclopropyl-5-(methoxycarbonyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(50 mg, 0.1 mmol) in CH₂Cl₂ (2 mL) was added DIBAL H (1M in toluene, 1mL, 1 mmol) at −78° C. The mixture was stirred at −78° C. for 1 h andthen rt for 1 h. Sat. NH₄Cl solution (5 mL) was added slowly at 0° C.and the mixture was filtered. The aqueous layer was extracted with EtOAc(3×5 mL). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by preparative TLC and then SFC separation to afford(R)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-5-yl)methanol(11.50 mg, 24.5% yield, isomer 1) as a colorless oil and(S)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-5-yl)methanol(7.10 mg, 15.1% yield, isomer 2) as a colorless oil.

Isomer 1:(R)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-5-yl)methanol.Analytical chiral HPLC: t_(R)=9.898 min in 15 min chromatography(Method: OD-H_3_5_40_2.35 ML). LC-MS MS (ESI) m/z 472.2 [M+H]⁺. ¹H NMR(CD₃OD 400 MHz): δ 8.23 (s, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 6.00 (d,J=8.0 Hz, 1H), 5.27-5.18 (m, 1H), 5.13 (s, 2H), 4.63 (s, 2H), 4.48-4.39(m, 1H), 4.23-4.11 (m, 1H), 3.85-3.73 (m, 1H), 3.28 (s, 3H), 2.58-2.42(m, 1H), 2.35-2.22 (m, 1H), 1.28 (d, J=6.8 Hz, 3H), 1.21-1.09 (m, 4H),1.05 (d, J=6.8 Hz, 3H).

Isomer 2:(S)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-5-yl)methanol.Analytical chiral HPLC: t_(R)=10.770 min in 15 min chromatography(Method: OD-H_3_5_40_2.35 ML). LC-MS MS (ESI) m/z 472.2 [M+H]⁺. ¹H NMR(G000237343 901-086-P1 CD₃OD 400 MHz): δ 8.23 (s, 1H), 8.18 (s, 1H),8.00 (s, 1H), 6.02 (d, J=8.0 Hz, 1H), 5.27-5.22 (m, 1H), 5.13 (s, 2H),4.64 (s, 2H), 4.47-4.40 (m, 1H), 4.23-4.11 (m, 1H), 3.85-3.74 (m, 1H),3.28 (s, 3H), 2.57-2.44 (m, 1H), 2.32-2.20 (m, 1H), 1.27 (d, J=6.8 Hz,3H), 1.21-1.09 (m, 4H), 1.05 (d, J=6.8 Hz, 3H).

Example 21(R)-(1-isopropyl-2-(5-methyl-4-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methanol

A mixture of (R)-methyl1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(45 mg, 0.128 mmol), 5-bromo-2-chloro-4-(trifluoromethyl)pyrimidine (40mg, 1.2eq.), DIPEA (90 μL, 4eq.) and DMF (1.5 mL) was put in MicrowaveOven and heated 90 min. at 130° C. The mixture was participated betweenEtOAc and water. The aqueous layer was extracted twice by EtOAc. Thecombined organic layers were washed by brine, dried over Na₂SO₄. Afterfiltration and concentration, the residue was purified by ISCO (12 gcolumn, 10-40% EtOAc in Hexanes) to afford 34.4 mg (47% yield) of(R)-methyl2-(4-bromo-3-(trifluoromethyl)phenyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate.

A mixture of (R)-methyl2-(5-bromo-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(7 mg, 0.012 mmol), Pd(PPh₃)₄ (1 mg, cat. Amount), 2M aq. K₂CO₃ solution(100 μL, excess), and dry 1,4-Dioxane (700 μL) was degassed and refilledwith nitrogen gas for 3 times. A solution of2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (5 mg, excess) in dry1,4-Dioxane (100 μL) was added. The mixture was heated in a microwaveoven for 30 minutes at 120° C. After concentration, the residue wasfiltered and purified by Gilson to afford 3.5 mg (R)-methyl1-isopropyl-2-(5-methyl-4-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(56% yield). LC-MS: m/z 512.3 [M+H]⁺.

A solution of (R)-methyl1-isopropyl-2-(5-methyl-4-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(3.5 mg, 0.007 mmol) in dry toluene (3 mL) was cooled to −78° C. Asolution of DIBAL-H in toluene (1M, 35 μL, 5 equiv.) was added. Themixture was stirred for 3 h. LC-MS indicated the reaction was complete.The mixture was quenched by sat. NH₄Cl solution (200 μL) and methanol(200 μL), before being warmed to r.t. After concentration, the residuewas filtered and purified by Gilson to afford 1.53 mg(R)-(1-isopropyl-2-(5-methyl-4-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methanol(46% yield). LC-MS: m/z 484.3 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz): δ 8.52(s, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 6.05 (d, J=8.0 Hz, 1H), 5.30 (dd,J=14.4 Hz, 4.8 Hz, 1H), 5.12 (s, 2H), 4.51 (dd, J=12.0 Hz, 3.2 Hz, 1H),4.22 (td, 12.0 Hz, 5.2 Hz, 1H), 3.88 (m, 1H), 3.26 (s, 1H), 2.57 (m,1H), 2.29 (s, 3H), 1.27 (d, 6.4 Hz, 3H), 1.06 (d, 6.4 Hz, 3H).

Example 22(R)-1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanoneand(S)-1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone

To a solution of1-isopropyl-7-(methylthio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (100mg, 0.38 mmol) and DIPEA (246.72 mg, 1.91 mmol) in i-PrOH (2 mL) wasadded 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (172.50 mg,0.76 mmol). The reaction mixture was stirred at rt overnight. Themixture was concentrated and purified by preparative TLC on silica geleluting with PE/EtOAc 1:1 to afford1-(2-(1-isopropyl-7-(methylthio)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone(120 mg, 69.67% yield) as a colorless oil. LC-MS MS (ESI) m/z 449.2[M+H]⁺. ¹H NMR (CDCl₃ 400 MHz): δ 8.66 (s, 1H), 7.44-7.40 (m, 1H), 7.06(d, J=8.4 Hz, 1H), 6.27-6.25 (m, 1H), 5.79-577 (m, 1H), 5.13-5.02 (m,1H), 4.21-4.16 (m, 1H), 3.97-3.91 (m, 1H), 3.82-3.71 (m, 1H), 2.48 (s,3H), 2.46 (s, 3H), 2.21-2.15 (m, 1H), 1.12-1.08 (m, 3H), 0.96-0.93 (m,3H).

To a solution of1-(2-(1-isopropyl-7-(methylthio)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone(110 mg, 0.23 mmol) in methanol (3 mL) at 0° C. was added NaMoO₄-2H₂O(107.61 mg, 0.49 mmol). The reaction mixture was stirred at 0° C. for 10min. Then H₂O₂ (5 mL, 30% wt) was added to the formed mixture. Themixture was stirred at rt for 1 h. The mixture was extracted with amixture solvent of dichloromethane (30 mL)/i-PrOH (10 mL) three times.The combined organic layers were concentrated, purified by preparativeTLC on silica gel eluting with PE/EtOAc 1:1 and purified by SFCseparation to afford(R)-1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone(26.90 mg, 22.38% yield, isomer 1) as a colorless oil and(S)-1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone(23.80 mg, 20.20% yield, isomer 2) as a colorless oil.

Isomer 1:(R)-1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone.Analytical chiral HPLC: t_(R)=7.972 min in 15 min chromatography(Method: AD-H_5_5_40_2.35 ML). LC-MS (ESI) m/z 481.2 [M+H]⁺, 503.1[M+Na]⁺. ¹H NMR (CDCl₃ 400 MHz): δ 8.75-8.73 (m, 1H), 7.95 (s, 1H), 7.72(d, J=8.4 Hz, 1H), 7.65 (d, J₁=8.4 Hz, J₂=1.6 Hz, 1H), 6.51-6.48 (m,1H), 5.94-5.92 (m, 1H), 5.25-5.22 (m, 1H), 4.41-4.36 (m, 1H), 4.15-4.10(m, 1H), 3.88-3.84 (m, 1H), 3.08 (s, 3H), 2.54 (s, 3H), 2.34-2.27 (m,1H), 1.21-1.18 (m, 3H), 1.06-1.05 (m, 3H).

Isomer 2:(R)-1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone.Analytical chiral HPLC: t_(R)=11.077 min in 15 min chromatography(Method: AD-H_5_5_40_2.35 ML). LC-MS MS (ESI) m/z 481.1 [M+H]⁺, 503.1[M+Na]⁺. ¹H NMR (CDCl₃ 400 MHz): δ 8.75-8.73 (m, 1H), 7.95 (s, 1H),7.73-7.70 (m, 1H), 7.65 (d, J₁=8.4 Hz, J₂=1.6 Hz, 1H), 6.51-6.48 (m,1H), 5.94-5.92 (m, 1H), 5.25-5.22 (m, 1H), 4.41-4.36 (m, 1H), 4.15-4.10(m, 1H), 3.88-3.84 (m, 1H), 3.08 (s, 3H), 2.54 (s, 3H), 2.34-2.27 (m,1H), 1.21-1.18 (m, 3H), 1.07-1.05 (m, 3H).

Example 23(R)-2-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-oland(S)-2-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol

To a solution of(R)-1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone(5 mg, 0.01 mmol) in THF (1 mL) was added LaCl₃-2LiCl (0.2 mL, 0.12mmol, 0.6M) at 0° C. under nitrogen. The reaction mixture was stirred at0° C. for 1 h. MeMgCl (0.3 mL, 0.9 mmol, 3M) was added to the formedmixture and then the reaction mixture was stirred at 0° C. for 1 h. Thereaction was quenched with sat. NH₄Cl (5 mL) at 0° C. and then extractedwith EtOAc (30 mL×3). The combined organic layers were dried overanhydrous Na2SO4, filtered and concentrated, purified by preparative TLCeluting with PE/EtOAc 1:1 and then by SFC separation to afford(R)-2-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol(1.20 mg, 24.68% yield, Isomer 1) as a colorless oil. Analytical chiralHPLC: t_(R)=6.394 min in 15 min chromatography (Method: OJ-H_3_5_40_2.35ML). LC-MS m/z 497.3 [M+H]⁺. ¹H NMR (CDCl₃ 400 MHz): δ 8.75 (s, 1H),7.93 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.62 (d, J₁=8.4 Hz, J₂=1.6 Hz,1H), 6.48 (s, 1H), 5.89 (d, J=8.8 Hz, 1H), 5.16-5.12 (m, 1H), 4.32-4.28(m, 1H), 4.14-4.07 (m, 1H), 3.86-3.77 (m, 1H), 3.07 (s, 3H), 2.34-2.25(m, 1H), 1.92 (s, 1H), 1.68 (s, 6H), 1.18 (d, J=7.2 Hz, 3H), 1.06 (d,J=7.2 Hz, 3H)

The(S)-2-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol(Isomer 2) was prepared in similar manner from(S)-1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone.Analytical chiral HPLC: t_(R)=7.631 min in 15 min chromatography(Method: AS-H_3_5_40_2.35 ML). LC-MS m/z 497.2 [M+H]⁺. ¹H NMR (CDCl₃ 400MHz): δ 8.75 (s, 1H), 7.93 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.62 (d,J₁=8.4 Hz, J₂=1.6 Hz, 1H), 6.48 (s, 1H), 5.89 (d, J=8.8 Hz, 1H),5.16-5.12 (m, 1H), 4.32-4.28 (m, 1H), 4.14-4.07 (m, 1H), 3.86-3.77 (m,1H), 3.07 (s, 3H), 2.34-2.25 (m, 1H), 1.92 (s, 1H), 1.68 (s, 6H), 1.18(d, J=7.2 Hz, 3H), 1.06 (d, J=7.2 Hz, 3H).

Example 241-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanol(4 isomers)

To a solution of1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone(10 mg, 21 μmol) in methanol (2 mL) was added NaBH₄ (7.8 mg, 0.21 mmol)at 0° C. The reaction mixture was stirred at reflux for 2 h. The mixturewas quenched with water (5 mL) and concentrated to remove methanol togive crude product which was extracted with EtOAc (30 mL×3). Thecombined organic layers were dried over anhydrous Na2SO4, filtered,concentrated and purified by preparative TLC on silica gel eluting withPE/EtOAc 1:1 and then by SFC separation to afford Isomer 1 (0.80 mg,7.97% yield) as a colorless oil, Isomer 2 (0.90 mg, 8.96% yield) as acolorless oil, Isomer 3 (1.20 mg, 11.95% yield) as a colorless oil andIsomer 4 (1.30 mg, 12.94% yield) as a colorless oil.

Isomer 1: Analytical chiral HPLC: t_(R)=3.16 min in 15 minchromatography (Method: AD-H_3_30%_2.35 ML). LC-MS m/z 483.0 [M+H]⁺. ¹HNMR (CDCl₃ 400 MHz): δ 8.83 (s, 1H), 7.93 (s, 1H), 7.68 (d, J=7.2 Hz,1H), 7.52 (d, J=7.2 Hz, 1H), 6.47 (s, 1H), 5.89 (d, J=8.8 Hz, 1H),5.24-5.14 (m, 2H), 4.33-4.31 (m, 1H), 4.16-4.09 (m, 1H), 3.85-3.81 (m,1H), 3.08 (s, 3H), 2.36-2.29 (m, 1H), 1.53-1.51 (m, 3H), 1.19 (d, J=6.4Hz, 3H), 1.07 (d, J=6.8 Hz, 3H).

Isomer 2: Analytical chiral HPLC: t_(R)=4.04 min in 15 minchromatography (Method: AD-H_3_30%_2.35 ML). LC-MS m/z 483.0 [M+H]⁺. ¹HNMR (CDCl₃ 400 MHz): δ 8.83 (s, 1H), 7.93 (s, 1H), 7.68 (d, J=7.2 Hz,1H), 7.52 (d, J=7.2 Hz, 1H), 6.47 (s, 1H), 5.89 (d, J=8.8 Hz, 1H),5.24-5.14 (m, 2H), 4.33-4.31 (m, 1H), 4.16-4.09 (m, 1H), 3.85-3.81 (m,1H), 3.08 (s, 3H), 2.36-2.29 (m, 1H), 1.53-1.51 (m, 3H), 1.19 (d, J=6.4Hz, 3H), 1.07 (d, J=6.8 Hz, 3H).

Isomer 3: Analytical chiral HPLC: t_(R)=6.08 min in 15 minchromatography (Method: AD-H_3_30%_2.35 ML). LC-MS m/z 483.0 [M+H]⁺. ¹HNMR (CDCl₃ 400 MHz): δ 8.83 (s, 1H), 7.93 (s, 1H), 7.68 (d, J=7.2 Hz,1H), 7.61 (d, J=7.2 Hz, 1H), 6.47 (s, 1H), 5.89 (d, J=8.8 Hz, 1H),5.24-5.14 (m, 2H), 4.33-4.31 (m, 1H), 4.16-4.09 (m, 1H), 3.85-3.81 (m,1H), 3.08 (s, 3H), 2.36-2.29 (m, 1H), 1.53-1.51 (m, 3H), 1.19 (d, J=6.4Hz, 3H), 1.07 (d, J=6.8 Hz, 3H).

Isomer 4: Analytical chiral HPLC: t_(R)=10.21 min in 15 minchromatography (Method: AD-H_3_30%_2.35 ML). LC-MS m/z 483.0 [M+H]⁺. ¹HNMR (CDCl₃ 400 MHz): δ 8.84 (s, 1H), 7.93 (s, 1H), 7.68 (d, J=7.2 Hz,1H), 7.61 (d, J=7.2 Hz, 1H), 6.47 (s, 1H), 5.89 (d, J=8.8 Hz, 1H),5.24-5.14 (m, 2H), 4.33-4.31 (m, 1H), 4.16-4.09 (m, 1H), 3.85-3.81 (m,1H), 3.08 (s, 3H), 2.36-2.29 (m, 1H), 1.53-1.51 (m, 3H), 1.19 (d, J=6.4Hz, 3H), 1.07 (d, J=6.8 Hz, 3H).

Example 25(R)-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanoland(S)-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanol

To a solution of1-isopropyl-7-(methylthio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (100mg, 0.38 mmol) and DIPEA (248.3 mg, 1.921 mmol) in i-PrOH (3 mL) wasadded ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (196mg, 0.77 mmol). The reaction mixture was stirred at rt overnight. Themixture was concentrated and purified by preparative TLC on silica geleluting with PE/EtOAc 1:1 to afford ethyl2-(1-isopropyl-7-(methylthio)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate(60 mg, 32.6% yield) as a colorless oil. LC-MS MS (ESI) m/z 478.7[M+H]⁺.

To a solution of ethyl2-(1-isopropyl-7-(methylthio)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate(54 mg, 0.11 mmol) in methanol (2 mL) at 0° C. was added NaMoO₄-2H₂O (54mg, 0.24 mmol). The reaction mixture was stirred at 0° C. for 10 min.H₂O₂ (2 mL, 30% wt) was added to the formed mixture. The mixture wasstirred at rt for 1 h. The mixture was extracted with a mixture solventof dichloromethane (30 mL)/i-PrOH (10 mL) three times. The combinedorganic layers were concentrated, purified by preparative TLC elutingwith PE/EtOAc 1:1 to afford ethyl2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate(25 mg, 43.39% yield) as a white solid. LC-MS MS (ESI) m/z 511.1 [M+H]⁺.

To a solution of2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate(25 mg, 0.05 mmol) in dichloromethane (1 mL) was added DIBAL-H (0.25 mg,0.25 mmol, 1M in toluene) at −78° C. under nitrogen. The reactionmixture was stirred at −78° C. for 1 h. The reaction was quenched withsat. NH₄Cl (5 mL) at −78° C. and then extracted with dichloromethane (30mL×3). The combined organic layers were concentrated, purified bypreparative TLC on silica gel eluting with PE/EtOAc 1:1 and then by SFCseparation to afford(R)-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanol(1.80 mg, 7.84% yield, isomer 1) as a colorless oil and(S)-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanol(1.60 mg, 6.97% yield, isomer 2) as a colorless oil.

Isomer 1:(R)-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanol.Analytical chiral HPLC: t_(R)=8.1 min in 15 min chromatography (Method:OD-3_5_5_40_2.5 ML). LC-MS m/z 469.0 [M+H]⁺. ¹H NMR (CDCl₃ 400 MHz): δ8.63 (s, 1H), 7.94 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.63 (d, J₁=8.4 Hz,J₂=1.6 Hz, 1H), 6.48 (s, 1H), 5.89 (d, J=8.8 Hz, 1H), 5.19-5.14 (m, 1H),4.71 (d, J=4.8 Hz, 2H), 3.86-3.82 (m, 1H), 4.14-4.07 (m, 1H), 3.86-3.77(m, 1H), 3.07 (s, 3H), 2.34-2.25 (m, 1H), 1.82-1.78 (m, 1H), 1.18 (d,J=7.2 Hz, 3H), 1.04 (d, J=7.2 Hz, 3H).

Isomer 2:(S)-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanol.Analytical chiral HPLC: t_(R)=11.33 min in 15 min chromatography(Method: OD-3_5_5_40_2.5 ML). LC-MS m/z 469.1 [M+H]⁺. ¹H NMR (CDCl₃ 400MHz): δ 8.63 (s, 1H), 7.94 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.63 (d,J₁=8.4 Hz, J₂=1.6 Hz, 1H), 6.48 (s, 1H), 5.89 (d, J=8.8 Hz, 1H),5.19-5.14 (m, 1H), 4.71 (s, 2H), 3.86-3.82 (m, 1H), 4.14-4.07 (m, 1H),3.86-3.77 (m, 1H), 3.07 (s, 3H), 2.34-2.25 (m, 1H), 1.82-1.78 (m, 1H),1.18 (d, J=7.2 Hz, 3H), 1.04 (d, J=7.2 Hz, 3H).

Example 26(±)-1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone

The intermediate8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indolewas prepared following a procedure analogous to that described inPreparation 4. The mixture of compound8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole(0.22 mmol), 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (100mg, 0.44 mmol) and DIEA (115 μL, 0.66 mmol) in i-PrOH/CH₂Cl₂ (2 mL/1 mL)was stirred at 60° C. for 15 h. The solvent was removed under reducedpressure and the residue was purified by column chromatography on silicagel eluting with EtOAc/hexanes (1/1) to give racemic1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone.LC-MS m/z 510 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.97 (s, 1H), 8.11 (s,1H), 7.80 (s, 1H), 6.54 (s, 1H), 6.01-5.90 (m, 1H), 5.25-5.15 (m, 1H),5.07 (s, 2H), 4.52-4.47 (m, 1H), 4.15-4.04 (m, 1H), 4.00-3.93 (m, 1H),3.26 (s, 3H), 2.55 (s, 3H), 2.41-2.32 (m, 1H), 1.18 (d, J=6.8 Hz, 3H),1.03 (d, J=6.8 Hz, 3H).

Example 27(R)-2-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-oland(S)-2-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol

To a solution of1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone(132 mg, 0.26 mmol) in CH₂Cl₂ (5 mL) was added pyridine (1 mL) and AcCl(130 μL, 1.3 mmol). The mixture was stirred at rt for 10 h. The reactionwas quenched with water (5 mL). The aqueous layer was extracted withCH₂Cl₂ (3×10 mL). The combined organic layers were washed with brine,and then dried over anhydrous Na₂SO₄. The mixture was filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel eluting with hexanes/EtOAc (1/1) to give(2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)methylacetate. LC-MS m/z 553 [M+H]⁺.

To a solution of(2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)methylacetate (37 mg, 67 μmol) in dry THF (2 mL) was added LaCl3.2 LiCl THFsolution (0.12 mL, 70 μmol). The resulting mixture was stirred for 20min at rt. The reaction mixture was cooled down to 0° C., MeMgCl in THFsolution (3.0 M, 0.15 mL) was added slowly and the reaction mixture wasallowed to stir at the same temperature for 0.5 h. Sat. aq. NH₄Cl (1 mL)and water (2 mL) were added. The aqueous layer was extracted with EtOAc(4×10 mL). Combined organic phases were dried (Na₂SO₄) and concentrated.The crude residue was purified by silica chromatography and SFCseparation to give isomers of2-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol.

Isomer 1: Analytical chiral HPLC: t_(R)=12.31 min in 15 minchromatography (Method: OD-H_5_5_40_2.35 ML). LC-MS m/z 527 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.83 (s, 1H), 8.08 (s, 1H), 7.77 (s, 1H), 6.50(s, 1H), 5.87 (d, J=8.4 Hz, 1H), 5.10 (m, 1H), 5.06 (s, 2H), 4.44-4.40(m, 1H), 4.09-4.02 (m, 1H), 3.91-3.84 (m, 1H), 3.26 (s, 3H), 2.36-2.29(m, 1H), 1.59 (s, 6H), 1.16 (d, J=6.8 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H).

Isomer 2: Analytical chiral HPLC: t_(R)=8.65 min in 15 minchromatography (Method: OD-H_5_5_40_2.35 ML). LC-MS m/z 527 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.83 (s, 1H), 8.08 (s, 1H), 7.77 (s, 1H), 6.50(s, 1H), 5.87 (d, J=8.4 Hz, 1H), 5.10 (m, 1H), 5.06 (s, 2H), 4.44-4.40(m, 1H), 4.09-4.02 (m, 1H), 3.91-3.84 (m, 1H), 3.26 (s, 3H), 2.36-2.29(m, 1H), 1.59 (s, 6H), 1.16 (d, J=6.8 Hz, 3H), 3 1.02 (d, J=6.8 Hz, 3H).

Example 28 (±)-Ethyl2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate

The intermediate8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indolewas prepared following a procedure analogous to that described inPreparation 4. The mixture of compound8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole(0.19 mmol), ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate(97 mg, 0.38 mmol) and DIEA (100 μL, 0.57 mmol) in i-PrOH/CH₂Cl₂ (1mL/0.5 mL) was stirred at 50° C. for 8 h. The solvent was removed underreduced pressure and the residue was purified by column chromatographyon silica gel eluting with EtOAc/hexanes (1/1) to give racemic ethyl2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate.LC-MS m/z 563 [M+Na]⁺. ¹H NMR (400 MHz, CD₃OD): δ 9.31 (s, 1H), 8.11 (s,1H), 7.80 (s, 1H), 6.55 (s, 1H), 6.02-5.92 (m, 1H), 5.23-5.17 (m, 1H),5.07 (s, 2H), 4.52-4.47 (m, 1H), 4.34 (q, J=7.2 Hz, 2H), 4.19-4.06 (m,1H), 4.00-3.93 (m, 1H), 3.27 (s, 3H), 2.42-2.32 (m, 1H), 1.36 (t, J=7.2Hz, 3H), 1.18 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H).

Example 29(R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamideand(S)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide

To a solution of ethyl2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate(30 mg, 55 μmol) in THF (1 mL) was added 1 N NaOH aqueous solution (1mL). The resulting mixture was stirred at rt for 3 h. The reactionmixture was acidified with 1N HCl solution (1.5 mL). The mixture wasextracted with CH₂Cl₂ (4×5 mL). The combined organic solution was washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to provide2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylicacid. It was used directly without further purification.

To a stirred solution of2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylicacid (55 μmol) in anhydrous DMF (1 mL) was added HATU (42 mg, 0.11mmol), NH₄Cl (30 mg, 0.55 mmol) and N,N-diisopropylethylamine (100 μL,0.55 mmol). The mixture was stirred at rt for 20 h. It was diluted withCH₂Cl₂ (10 mL) and washed with H₂O. The organic layer was separated, andthe aqueous layer was extracted with CH₂Cl₂ (3×10 mL). The combinedorganic solution was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude residue waspurified by silica chromatography and SFC separation to give isomers of2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide.

Isomer 1: Analytical chiral HPLC: t_(R)=2.92 min in 8 min chromatography(Method: AS-H_S_3_40_3 ML). LC-MS m/z 494 [M+H−18]⁺, 512 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): δ 8.68 (s, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 6.54 (s,1H), 6.00-5.87 (m, 1H), 5.20-5.08 (m, 1H), 5.07 (s, 2H), 4.50-4.46 (m,1H), 4.14-4.08 (m, 1H), 3.98-3.90 (m, 1H), 3.27 (s, 3H), 2.39-2.32 (m,1H), 1.29 (s, 2H), 1.18 (d, J=6.8 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H).

Isomer 2: Analytical chiral HPLC: t_(R)=4.91 min in 8 min chromatography(Method: AS-H_S_3_40_3 ML). LC-MS m/z 494 [M+H−18]⁺, 512 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): δ 8.68 (s, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 6.54 (s,1H), 6.00-5.87 (m, 1H), 5.20-5.08 (m, 1H), 5.07 (s, 2H), 4.50-4.46 (m,1H), 4.14-4.08 (m, 1H), 3.98-3.90 (m, 1H), 3.27 (s, 3H), 2.39-2.32 (m,1H), 1.29 (s, 2H), 1.18 (d, J=6.8 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H).

Example 30 (R)-methyl2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate

The title compound was prepared by a procedure analogous to thosedescribed in Example 12 by using methyl2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate instead of ethyl2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate as a reagent. LC-MSm/z 528 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 9.04 (s, 1H), 8.25 (s, 1H),7.96 (s, 1H), 6.12-6.06 (m, 1H), 5.46-5.34 (m, 1H), 5.11 (s, 2H), 4.54(dd, J₁=12.4 Hz, J₂=3.2 Hz, 1H), 4.24 (td, J₁=12.0 Hz, J₂=5.2 Hz, 1H),3.95 (dddd, J₁=14.4 Hz, J₂=12.0 Hz, J₃=4.4 Hz, 1H), 3.89 (s, 3H), 3.26(s, 3H), 2.64-2.54 (m, 1H), 1.29 (d, J=6.8 Hz, 3H), 1.07 (d, J=6.8 Hz,3H).

Example 31 LXR α/β Radioligand Binding Assay

Compounds of the invention were assessed in a competition binding assaywhere different concentrations of compounds were incubated with the LXRligand binding domain (LBD) in the presence of radiolabeled LXR ligand[³H]TO901317. The amount of the LXR-LBD that complexed with [³H]T0901317was measured by scintillation proximity assay (SPA) employingnon-specific binding of LXR-LBD to poly-lysine coated Yttrium silicatebeads. Partially purified LXR α or β LBD protein (15-45 nM) wasincubated at rt for 30 min with 15 nM [³H]T0901317 (25-40 Ci/mmol) anddifferent concentrations of test compounds in 80 μL of phosphatebuffered saline (PBS) buffer containing 2.5% DMSO, 1% glycerol, 2 mMEDTA, 2 mM CHAPS and 5 mM DTT in 96-well plates. Poly-lysine SPA beads(50 μg) were added to each well and the total volume was adjusted to 120μL. The plates were shaken on an orbital shaker for 20 min and thenallowed to settle for 10 more minutes at rt before a briefcentrifugation at 2,000 rpm for 1 min. The SPA signal was measured on aMicroBeta® liquid scintillation counter (Perkin Elmer, Waltham, Mass.),and the results were used for calculating IC50 values based on the totalbinding (DMSO control) and non-specific binding (5 μM of unlabeledT0901317) controls. The K_(i) values were calculated according toequation 1, where [RL] is the final concentration of [³H]T0901317 in theassay, and the K_(d) values of 20 nM and 10 nM of TO901317 for LBDs ofLXRα and LXRβ, respectively, were determined by direct titration of theradioligand with these proteins.

$\begin{matrix}{{Ki} = \frac{{IC}\; 50}{\left( {1 + \frac{\lbrack{RL}\rbrack}{Kd}} \right)}} & (1)\end{matrix}$

Example 32 LXR Luciferase Transcriptional Reporter Gene Assay

The LXR luciferase transcriptional reporter gene assay measures theability of LXR ligands to promote transcriptional activation via theligand binding domain (LBD) of LXR. HEK293 cells were grown in DMEMmedium containing 10% FBS (Gibco®, #11995-065) and 1×PenStrep (Gibco®,#15140) at 37° C. in 5% CO₂ atmosphere. 90% confluent cells from a 150mm dish were seeded in six 100 mm dishes. The cells werebatch-transfected with an expression plasmid containing the Gal4 DNAbinding domain fused to either the LBD of LXRα or LXRβ and a luciferasereporter plasmid pG5-Luc (Promega, Madison, Wis.), which has Gal4response elements upstream of firefly luciferase gene (luc+).Transfection was accomplished with Lipofectamine™ 2000 (Gibco®)according to the manufacturer's suggested protocol. Five hs followingtransfection, 15 mL of 10% charcoal-treated FBS (Hyclone, #SH30070.03)in DMEM were added to the transfected dishes without removingtransfection media, and then incubate the cells at 37° C. overnight. Thenext day, the cells from the transfected dish were trypsinized, washedwith PBS, resuspended in 10% charcoal-treated DMEM media and plated into96-well plates with 60,000 cells/100 μL per well. The cells wereincubated at 37° C. for ˜4 h before addition of 100 μL of test compoundor control ligand at different concentrations (final DMSO concentrationat 0.2%). Following incubation of the cells for 16 h with substances,the culture media were dumped and Bright-Glo™ luciferase reagent(Promega, Cat. #E2610) was added to lyse the cells and initiate theluciferase reaction. Luminescence, as a measure of luciferase activity,was detected in a plate reader (Victor2, PE-Wallac). Transcriptionalactivation in the presence of a test substance was expressed asfold-change in luminescence compared to that of cells incubated in theabsence of the substance. EC50 values were calculated using the XLfit™program (IDBS, Guilford, UK).

Example 33

Compounds of the invention were tested as described in Examples 31 and32. The biological data are presented in the table below.

LXRα LXRβ BINDING K_(i) BINDING K_(i) LXRα CELL LXRβ CELL Compound (nM)(nM) EC50 (nM) EC50 (nM) E1 1400 191 1580 350 E2 1600 176 2370 377E3 >3330 1160 17300 4620 E4 1540 137 2100 293 E5 >3330 >2500 >20000 2690E6a 277 14 294 21 E6b >3330 1190 8530 931 E7a 253 14 289 23E7b >3330 >2500 17300 2180 E8a >3330 1650 14900 2040 E8b 74 13 224 21E8c 65 9 216 19 E8d >3330 1330 13800 2040 E9a 136 17 294 16 E9b >33301360 >20000 1340 E10a >3330 >2500 >20000 2400 E10b 72 7 290 26 E10c 1067 171 12 E10d >3330 1940 >20000 1660 E11a 160 14 394 68 E11b 236 23 1040103 E12 49 6 300 50 E13a 409 17 475 45 E13b >3330 1040 10200 1045E14a >3330 >2500 >20000 7540 E14b >3330 >2500 >20000 >20000 E15a >3330240 >20000 >20000 E15b >3330 >2500 >20000 >20000 E16a >3330 376 >200001730 E16b >3330 >2500 >20000 >20000 E17a 2130 220 5360 >20000E17b >3330 >2500 >20000 4900 E18 70 8 154 24E19 >3330 >2500 >20000 >20000 E20a 1764 110 >20000 >20000E20b >3330 >2500 >20000 >20000 E21 83 10 116 10 E22a 149 12 690 107E22b >3330 >2500 >20000 11500 E23a 237 21 1480 306 E23b >33302440 >20000 1340 E24a 56 7 529 134 E24b 198 20 1010 150 E24c >33301690 >20000 18200 E24d >3330 >2500 >20000 >20000 E25a 83 6 562 83E25b >3330 >2500 >20000 10800 E26 46 7 259 16 E27a 23 2 88 10 E27b 3240712 3600 1440 E28 26 5 336 72 E29a 987 50 2290 >20000 E29b >3330 >250012700 3290 E30 129 10 266 17

What is claimed is:
 1. A compound represented by the followingstructural formula:

or a pharmaceutically acceptable salt thereof, wherein: X is N orCR^(c); R¹ is alkyl or —NR^(a)R^(b); R² is H; halogen; —CN; —NRC(O)R;—C(O)OR; —C(O)NR^(a)R^(b); monocyclic heteroaromatic optionallysubstituted with one or more groups selected from alkyl, —CN, —NRC(O)R,—C(O)OR, —C(O)NR^(a)R^(b) and halogen; monocyclic non-aromaticheterocycle optionally substituted with one or more groups selected fromalkyl, halogen, —CN and ═O; or alkyl optionally substituted by one ormore groups selected from halogen, hydroxy, alkoxy, —NR^(a)R^(b),—NRC(O)R, —NRC(O)O(alkyl), —NRC(O)N(R)₂, —C(O)OR, thiol, alkylthiol,nitro, —CN, ═O, —OC(O)H, —OC(O)(alkyl), —OC(O)O(alkyl), —OC(O)N(R)₂ and—C(O)NR^(a)R^(b); R³ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, monocyclic non-aromatic heterocycle, monocyclicheteroaromatic or phenyl, wherein the phenyl, monocyclic non-aromaticheterocycle and monocyclic heteroaromatic group represented by R³ areoptionally substituted with one or more groups selected from alkyl,halogen, haloalkyl, alkoxy, haloalkoxy, nitro and —CN; R⁴ is halogen,—CN, —OR, —SR, —N(R)₂, —C(O)R, —C(O)OR, —OC(O)O(alkyl),—C(O)O(haloalkyl), —OC(O)R, —C(O)N(R)₂, —OC(O)N(R)₂, —NRC(O)R,—NRC(O)O(alkyl), —S(O)R, —SO₂R, —SO₂N(R)₂, —NRS(O)R, —NRSO₂R,—NRC(O)N(R)₂, —NRSO₂N(R)₂, haloalkyl, haloalkoxy, cycloalkoxy,cycloalkyl, monocyclic non-aromatic heterocycle, monocyclicheteroaromatic or alkyl, wherein the alkyl, monocyclic non-aromaticheterocycle and monocyclic heteroaromatic group represented by R⁴ isoptionally substituted with one or more groups selected from —CN, —OR,—SR, —N(R)₂, ═O, —C(O)R, —C(O)OR, —C(O)O(haloalkyl), —OC(O)R,—OC(O)O(alkyl), —C(O)N(R)₂, —OC(O)N(R)₂, —NRC(O)R, —NRC(O)O(alkyl),—S(O)R, —SO₂R, —SO₂N(R)₂, —NRS(O)R, —NRSO₂R, —NRC(O)N(R)₂ and—NRSO₂N(R)₂; R⁵ is halogen, —CN, —OR, —SR, —N(R)₂, —C(O)R, —C(O)OR,—OC(O)O(alkyl), —C(O)O(haloalkyl), —OC(O)R, —C(O)N(R)₂, —OC(O)N(R)₂,—NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO₂R, —SO₂N(R)₂, —NRS(O)R, —NRSO₂R,—NRC(O)N(R)₂, —NRSO₂N(R)₂, haloalkyl, haloalkoxy, cycloalkoxy,cycloalkyl, monocyclic non-aromatic heterocycle, monocyclicheteroaromatic or alkyl, wherein the monocyclic non-aromatic heterocycleand monocyclic heteroaromatic group represented by R⁵ is optionallysubstituted with one or more groups selected from —CN, —OR, —SR, —N(R)₂,═O, —C(O)R, —C(O)OR, —C(O)O(haloalkyl), —OC(O)R, —OC(O)O(alkyl),—C(O)N(R)₂, —OC(O)N(R)₂, —NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO₂R,—SO₂N(R)₂, —NRS(O)R, —NRSO₂R, —NRC(O)N(R)₂ and —NRSO₂N(R)₂, and whereinthe alkyl represented by R⁵ is substituted with one or more groupsselected from —CN, —OR, —SR, —N(R)₂, ═O, —C(O)R, —C(O)OR,—C(O)O(haloalkyl), —OC(O)R, —OC(O)O(alkyl), —C(O)N(R)₂, —OC(O)N(R)₂,—NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO₂R, —SO₂N(R)₂, —NRS(O)R, —NRSO₂R,—NRC(O)N(R)₂ and —NRSO₂N(R)₂; R⁶ is H, halogen, —CN, —OR, —SR, —N(R)₂,—C(O)R, —C(O)OR, —OC(O)O(alkyl), —C(O)O(haloalkyl), —OC(O)R, —C(O)N(R)₂,—OC(O)N(R)₂, —NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO₂R, —SO₂N(R)₂,—NRS(O)R, —NRSO₂R, —NRC(O)N(R)₂, —NRSO₂N(R)₂, haloalkyl, haloalkoxy,cycloalkoxy, cycloalkyl or alkyl, wherein the alkyl group represented byR⁶ is optionally substituted with one or more groups selected from —CN,—OR, —SR, —N(R)₂, ═O, —C(O)R, —C(O)OR, —C(O)O(haloalkyl), —OC(O)R,—OC(O)O(alkyl), —C(O)N(R)₂, —OC(O)N(R)₂, —NRC(O)R, —NRC(O)O(alkyl),—S(O)R, —SO₂R, —SO₂N(R)₂, —NRS(O)R, —NRSO₂R, —NRC(O)N(R)₂ and—NRSO₂N(R)₂; or R⁵ and R⁶, taken together with the carbon atoms to whichthey are bonded, form a moncyclic non-aromatic heterocycle optionallysubstituted with one or more groups selected from alkyl, halogen,hydroxyalkyl, alkoxyalkyl, haloalkyl and ═O; and each R independently isH or alkyl; R^(a) and R^(b) are independently H, alkyl or R^(a) andR^(b) can be taken together with the nitrogen to which they are attachedto form a monocyclic non-aromatic heterocycle; and R^(c) is H, alkyl, orhalogen.
 2. The compound of claim 1, wherein: R³ is alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, or phenyl, wherein the phenylgroup represented by R³ is optionally substituted with one or moregroups selected from alkyl, halogen, haloalkyl, alkoxy, haloalkoxy,nitro and —CN; R⁴ is halogen, —CN, —OR, —SR, —N(R)₂, —C(O)R, —C(O)OR,—OC(O)O(alkyl), —C(O)O(haloalkyl), —OC(O)R, —C(O)N(R)₂, —OC(O)N(R)₂,—NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO₂R, —SO₂N(R)₂, —NRS(O)R, —NRSO₂R,—NRC(O)N(R)₂, —NRSO₂N(R)₂, haloalkyl, haloalkoxy, cycloalkoxy,cycloalkyl or alkyl, wherein the alkyl represented by R⁴ is optionallysubstituted with one or more groups selected from —CN, —OR, —SR, —N(R)₂,═O, —C(O)R, —C(O)OR, —C(O)O(haloalkyl), —OC(O)R, —OC(O)O(alkyl),—C(O)N(R)₂, —OC(O)N(R)₂, —NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO₂R,—SO₂N(R)₂, —NRS(O)R, —NRSO₂R, —NRC(O)N(R)₂ and —NRSO₂N(R)₂; R⁵ ishalogen, —CN, —OR, —SR, —N(R)₂, —C(O)R, —C(O)OR, —OC(O)O(alkyl),—C(O)O(haloalkyl), —OC(O)R, —C(O)N(R)₂, —OC(O)N(R)₂, —NRC(O)R,—NRC(O)O(alkyl), —S(O)R, —SO₂R, —SO₂N(R)₂, —NRS(O)R, —NRSO₂R,—NRC(O)N(R)₂, —NRSO₂N(R)₂, haloalkyl, haloalkoxy, cycloalkoxy,cycloalkyl or alkyl, wherein the alkyl represented by R⁵ is substitutedwith one or more groups selected from —CN, —OR, —SR, —N(R)₂, ═O, —C(O)R,—C(O)OR, —C(O)O(haloalkyl), —OC(O)R, —OC(O)O(alkyl), —C(O)N(R)₂,—OC(O)N(R)₂, —NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO₂R, —SO₂N(R)₂,—NRS(O)R, —NRSO₂R, —NRC(O)N(R)₂ and —NRSO₂N(R)₂; R⁶ is H, halogen, —CN,—OR, —SR, —N(R)₂, —C(O)R, —C(O)OR, —OC(O)O(alkyl), —C(O)O(haloalkyl),—OC(O)R, —C(O)N(R)₂, —OC(O)N(R)₂, —NRC(O)R, —NRC(O)O(alkyl), —S(O)R,—SO₂R, —SO₂N(R)₂, —NRS(O)R, —NRSO₂R, —NRC(O)N(R)₂, —NRSO₂N(R)₂,haloalkyl, haloalkoxy, cycloalkoxy, cycloalkyl or alkyl, wherein thealkyl group represented by R⁶ is optionally substituted with one or moregroups selected from —CN, —OR, —SR, —N(R)₂, ═O, —C(O)R, —C(O)OR,—C(O)O(haloalkyl), —OC(O)R, —OC(O)O(alkyl), —C(O)N(R)₂, —OC(O)N(R)₂,—NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO₂R, —SO₂N(R)₂, —NRS(O)R, —NRSO₂R,—NRC(O)N(R)₂ and —NRSO₂N(R)₂.
 3. The compound of claim 2, wherein thecompound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim3, wherein the compound is represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim4, wherein the compound is represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim5, wherein the compound is represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim4, wherein the compound is represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim7, wherein the compound is represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim8, wherein: R¹ is methyl or —NH₂; R² is H or methyl, wherein the methylgroup represented by R² is optionally substituted with one or moregroups selected from halogen, hydroxy, alkoxy, —NR^(a)R^(b), —NRC(O)R,—NRC(O)O(alkyl), —NRC(O)N(R)₂, —C(O)OR, thiol, alkylthiol, nitro, —CN,═O, —OC(O)H, —OC(O)(alkyl), —OC(O)O(alkyl), —C(O)NR^(a)R^(b) and—OC(O)N(R)₂; R³ is methyl, ethyl, propyl, isopropyl, tert-butyl,sec-butyl, iso-butyl, —CH₂CF₃, —CH(CH₂F)₂, —CH(CHF₂)₂, —CH(CF₃)₂,—CF(CH₃)₂, —CF₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,—C(OH)(CH₃)₂, —CH(OH)(CH₃), or phenyl, wherein the phenyl grouprepresented by R³ is optionally substituted with one or more groupsselected from alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, nitro and—CN; and R^(c), where present, is H.
 10. The compound of claim 9,wherein R² is H or —CH₂OH.
 11. The compound of claim 10, wherein: R¹ ismethyl; R² is —CH₂OH; and R³ is isopropyl.
 12. The compound of claim 11,wherein R⁴ is halogen, hydroxy, alkyl, cycloalkyl, cycloalkoxy, alkoxy,haloalkoxy, haloalkyl, —N(R)₂, —C(O)OH, —C(O)O(alkyl),—C(O)O(haloalkyl), —C(O)(alkyl), —C(O)N(R)₂, —NRC(O)R, —SO₂N(R)₂,—OC(O)N(R)₂, —CN, hydroxyalkyl or dihydroxyalkyl; and R⁵ is halogen,hydroxy, cycloalkyl, cycloalkoxy, alkoxy, haloalkoxy, haloalkyl, —N(R)₂,—C(O)OH, —C(O)O(alkyl), —C(O)O(haloalkyl), —C(O)(alkyl), —C(O)N(R)₂,—NRC(O)R, —SO₂N(R)₂, —OC(O)N(R)₂, —CN, hydroxyalkyl or dihydroxyalkyl.13. The compound of claim 12, wherein R⁴ is methyl, ethyl, hydroxy, CF₃,isopropyl, cyclopropyl, —CH₂OH, —CH(OH)(CH₂)(OH), —C(OH)(CH₃)₂,—CH(OH)(CH₃), —CH(OH)(CH₂)(CH₃), —CH(OH)(CH₂)₂(CH₃), —C(O)NH₂,—C(O)N(CH₃)₂, —C(O)OH, —C(O)NH(CH₃), —C(O)CH₃, —C(O)CH₂CH₃,—C(O)O(CH₂)(CH₃), —C(O)O(tert-butyl), —C(O)O(C)(CH₃)₂(CF₃), —NHC(O)CH₃,—OCHF₂, —OCF₃, —OCH₂CH₃, —OCH(CH₃)₂ or —OCH₃; and R⁵ is hydroxy, CF₃,cyclopropyl, —CH₂OH, —CH(OH)(CH₂)(OH), —C(OH)(CH₃)₂, —CH(OH)(CH₃),—CH(OH)(CH₂)(CH₃), —CH(OH)(CH₂)₂(CH₃), —C(O)NH₂, —C(O)N(CH₃)₂, —C(O)OH,—C(O)NH(CH₃), —C(O)CH₃, —C(O)CH₂CH₃, —C(O)O(CH₂)(CH₃),—C(O)O(tert-butyl), —C(O)O(C)(CH₃)₂(CF₃), —NHC(O)CH₃, —OCHF₂, —OCF₃,—OCH₂CH₃, —OCH(CH₃)₂ or —OCH₃.
 14. The compound of claim 13, wherein R⁴is alkyl, haloalkyl, cycloalkyl, alkoxy, or haloalkoxy.
 15. The compoundof claim 14, wherein R⁴ is methyl, halogenated methyl, cyclopropyl,—OCHF₂ or —OCH₃.
 16. The compound of claim 15, wherein R⁴ is CF₃. 17.The compound of claim 16, where R⁵—C(OH)(CH₃)₂.
 18. The compound ofclaim 1, wherein the compound is represented by a structural formulaselected from

or a pharmaceutically acceptable salt thereof.
 19. A pharmaceuticalcomposition comprising a pharmaceutical carrier or diluent and thecompound of claim
 1. 20. A compound represented by the followingstructural formula:

or a salt thereof, wherein: X is N or CR^(c); R¹⁰ is alkyl or—NR^(a)R^(b); R²⁰ is H; halogen; —CN; —NRC(O)R; —C(O)OR;—C(O)NR^(a)R^(b); monocyclic heteroaromatic optionally substituted withone or more groups selected from alkyl, —CN, —NRC(O)R, —C(O)OR,—C(O)NR^(a)R^(b) and halogen; monocyclic non-aromatic heterocycleoptionally substituted with one or more groups selected from alkyl,halogen, —CN and ═O; or alkyl optionally substituted by one or moregroups selected from halogen, hydroxy, alkoxy, —NR^(a)R^(b), —NRC(O)R,—NRC(O)O(alkyl), —NRC(O)N(R)₂, —C(O)OR, thiol, alkylthiol, nitro, —CN,═O, —OC(O)H, —OC(O)(alkyl), —OC(O)O(alkyl), —OC(O)N(R)₂,—C(O)NR^(a)R^(b), and —O (protecting group); R³⁰ is alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl or phenyl, wherein the phenylgroup represented by R³⁰ is optionally substituted with one or moregroups selected from alkyl, haloalkyl, alkoxy, haloalkoxy, nitro and—CN; each R independently is H or alkyl; R^(a) and R^(b) areindependently H, alkyl or R^(a) and R^(b) can be taken together with thenitrogen to which they are attached to form a monocyclic non-aromaticheterocycle; and R^(c) is H, alkyl, or halogen.
 21. The compound ofclaim 20, wherein the compound is represented by the followingstructural formula:

or a salt thereof.
 22. The compound of claim 21, wherein the compound isrepresented by the following structural formula:

or a salt thereof.
 23. The compound of claim 21, wherein the compound isrepresented by the following structural formula:

or a salt thereof.
 24. The compound of claim 23, wherein R¹⁰ is —CH₃.25. The compound of claim 24, wherein R²⁰ is —CH₂OH, —CH₂O (protectinggroup), —COOH, or —C(O)O(alkyl).
 26. The compound of claim 25, whereinR³⁰ is isopropyl.
 27. The compound of claim 26, wherein R²⁰ is—CH₂O(TBDPS) or —C(O)OCH₃.